Pharmaceutical compositions and kits containing immunomodulatory agents for treating disease

Abstract

The present invention relates to an immunomodulatory substance and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, the method comprising the steps of causing accumulation of PBMCs in the skin, causing dilation of capillaries in the skin, causing an increase in blood volume in the skin, increasing sO 2 the method includes step (A) selected from one or more of: causing an increase in Hb in the skin, causing an increase in temperature on the skin, causing redness on the skin, administering conditioning energy to the skin, administering a skin conditioning agent to the skin, or administering PBMCs to the skin of the subject, and the method further includes step (B) administering a first immunomodulatory agent to the skin of the subject and / or step (C) administering a second immunomodulatory agent to the skin of the subject.

Description

[Technical Field]

[0001] The present invention relates to immunomodulatory and / or skin-conditioning agents for use in methods for treating and / or preventing diseases in a subject, such as inflammatory, immunological and / or autoimmune diseases.

[0002] The present invention further relates to pharmaceutical compositions, topical dosage forms, injectable dosage forms, and kits comprising the immunomodulatory and / or skin conditioning agents that can be used in methods for treating and / or preventing disease in a subject. Additionally, the present invention relates to medical devices and kits (kits of parts) that can be used in methods for treating and / or preventing disease in a subject. [Background technology]

[0003] Inflammatory, immunological, and / or autoimmune diseases that cause damaging and painful inflammatory responses that have a profound impact on quality of life are widespread, affecting a significant portion of the human and animal populations. In particular, the chronic course of such diseases can cause extreme suffering over long periods of time to affected subjects and frequently shortens their lifespan.

[0004] Known methods and substances for the treatment and prevention of such diseases are still largely unsatisfactory. For example, glucocorticoids are used to treat these diseases; however, apart from their beneficial effect of reducing inflammation, they have significant negative side effects, especially with long-term use. For example, when using biologics and biosimilars, such as monoclonal antibodies, this method is also very expensive, is poorly tolerated by many patients, does not work in a significant proportion of patients, and often loses its effectiveness after a certain period of time.

[0005] On the other hand, immunotherapy may be available, however, it requires significant human and material resources and can only be provided in specialized medical facilities. Therefore, immunotherapy involves patient travel to a medical facility or is not accessible at all. Therefore, such therapy is not suitable for widespread public use, is time-consuming, and cannot be marketed as a readily available therapy. Summary of the Invention [Problem to be solved by the invention]

[0006] It is therefore highly desirable, and therefore an object of the present invention, to provide alternative agents, articles and methods for the treatment and / or prevention of inflammatory, immunological and / or autoimmune diseases. [Means for solving the problem]

[0007] Quite surprisingly, it has been found that this object can be achieved by the use of immunomodulatory substances in a manner that brings them into close proximity and / or contact with peripheral blood mononuclear cells (PBMCs) and incubates them in vivo in a body part of a subject, such as the skin.

[0008] The present invention is based on completely novel principles discovered for the treatment and / or prevention of inflammatory, immunological, and / or autoimmune diseases, and has numerous benefits for the treated subjects. Thus, the present invention provides a novel platform technology that is broadly applicable to the treatment of inflammatory, immunological, and / or autoimmune diseases.

[0009] The following definitions and preferred embodiments generally relate to any of the embodiments as described herein unless otherwise stated, even if not explicitly mentioned and even if described under a different subject or summary description.

[0010] In particular, the present invention is based on the surprising discovery that PBMCs, typically immune cells such as lymphocytes, and more particularly naive lymphocytes such as naive T cells, must accumulate, for example, within the skin, and that the PBMCs must be brought into close proximity and / or contact with the administered immunomodulatory substance. The present invention is based on the further surprising discovery that the administration of an immunomodulatory substance must be combined with the generation of vasodilation (dilation of blood vessels, particularly capillary dilation), increasing blood volume, increasing sO2 (oxygen saturation of hemoglobin), increasing rHb (relative hemoglobin), increasing temperature, causing redness, or administering conditioning energy, such as administering a skin conditioning agent into / on / to the skin. Accordingly, without wishing to be bound by theory, it is believed that PBMCs accumulate, for example, within the skin, and that the PBMCs must be brought into close proximity and / or contact with the administered immunomodulatory substance. In this way, the skin can be used as an in vivo incubator for PBMCs, which is thought to allow the affected PBMCs to exert modulated immune system activity.

[0011] The general concept of the present invention is to provide the following steps: (A-0) causing accumulation of PBMCs (peripheral blood mononuclear cells) in a body part of a subject, preferably in the skin; (A-1) causing capillary dilation in a body part, preferably in the skin, of a subject; (A-2) causing an increase in blood volume in a body part of a subject, preferably in the skin; (A-3) increasing sO2 (oxygen saturation of hemoglobin) in a body part, preferably the skin, of a subject and / or increasing rHb (relative hemoglobin) in a body part, preferably the skin, of a subject; (A-4) generating a temperature increase on a body part, preferably on the skin, of a subject; (A-5) causing redness on a body part, preferably the skin, of a subject; (A-6) applying conditioning energy to a body part, preferably the skin, of a subject; (A-7) administering a skin conditioning agent to a body part, preferably the skin, of a subject; and / or (A-8) Administering PBMCs into a body part, preferably the skin, of a subject and the steps of: (B) administering an immunomodulatory agent to said body part of the subject; and / or (C) administering an immunomodulatory agent to said body part of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). The present invention relates to a method of manufacturing a semiconductor device, comprising the steps of:

[0012] The present invention therefore provides an immunomodulatory and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: The method includes step (A), which comprises: (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 in the skin of the subject and / or increasing rHb in the skin of the subject; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method comprises the steps of: (B) administering an immunomodulatory agent to the skin of the subject; and / or (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). The present invention relates to an immunomodulatory and / or skin conditioning agent, and to such methods, further comprising:

[0013] The present invention also relates to pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and kits according to the independent claims and as mentioned in more detail below.

[0014] The present invention is highly effective in the treatment and / or prevention of inflammatory, immunological and / or autoimmune diseases. The present invention aims, among others, to control joint inflammation and thus prevent or delay future joint deformities caused thereby. Advanced joint deformities often necessitate joint replacement surgery in the long term, which can be delayed or in some cases completely eliminated.

[0015] Furthermore, the present invention has no adverse side effects, meaning that the present invention can also contribute to the mental and / or physical well-being of the treated subject, prolonging their lifespan while maintaining an improved quality of life.

[0016] Furthermore, the present invention is easy and fast to implement, for example, because step (A) and steps (B) and / or (C) are performed on and / or within the skin. The skin has the advantage of being easily accessible for treatment and administration. A further advantage is that treatments on the skin, such as balms, creams, or salves, or within the skin, such as injections, generally pose relatively low health risks to the subject, as, for example, intravenous injections.

[0017] The present invention provides readily available immunotherapeutic agents without the need for specialized medical facilities. This simultaneously keeps costs low by ensuring high patient compliance. In some embodiments of the invention, subjects or animal owners can self-apply the method steps, allowing for on-site application of therapy to immobile humans or animals that are unable or unwilling to be transported. Thus, the present invention provides a therapy that is accessible to patients living in remote locations beyond the reach of medical facilities.

[0018] Furthermore, the present invention is performed without administering extracts of the subject's own body, such as body fluids, blood, cells, tissues, PBMCs, substances, etc. (except in the case of administering PBMCs). Such extracts can be mixed up or contaminated, for example, during storage, freezing, or ex vivo incubation, for example, in cell culture. Traditional immunotherapy frequently uses cell culture, which is performed ex vivo. The present invention transfers the cell culture into the subject's body, whereby incubation occurs using the subject's body, particularly the skin, as an in vivo incubator. Therefore, with the present invention, there is no risk of contamination or mix-up of such extracts, or the risk is at least minimized.

[0019] More advantageously, this allows PBMC to remain in its natural habitat under optimal conditions and in optimal microenvironment, for example, by providing it into the skin.This means that PBMC is not exposed to any stress caused by extraction, freezing, temperature fluctuation, CO2 environment content, nutrient supply and medium composition, all of which may cause altered expression pattern or even the death of part of cell population.In addition, it does not require the expensive materials and advanced equipment required for traditional cell culture.

[0020] A further advantage is that therapy can be provided in a manner that does not require user training to perform the method or that compensates for insufficient user training. The process and implementation of the method can be designed to be very simple and concise, ensuring accurate implementation of the method. This may be particularly important for very young or elderly patients, or for users with impaired manual skills, as is often the case in cases involving rheumatic diseases, for example. Furthermore, the risk of self-application errors can be eliminated, and poor adherence to treatment can be reduced or even overcome due to the uncomplicated availability of a method that is simple to apply and does not require frequent hospital visits. The percentage of patients who respond to the therapy of the present invention is very high. The present invention, as previously known, does not result in any adverse side effects or intolerance. On the contrary, patients feel reassured and even more energetic. Such adverse side effects or intolerance are also not expected, even with long-term use. Furthermore, a decrease in efficacy with long-term use, which is often the case with, for example, biologics, is also not expected with the therapeutic approach of the present invention. The method is therefore highly suitable for finding widespread and sustained public application.

[0021] Furthermore, the therapies according to the present invention are compatible with and offer advantages and additional benefits over conventional preparations, medicines, and drugs, including biologics, biosimilars, glucocorticoids, and methotrexate (MTX), and can even completely replace or supplant these preparations without any side effects, intolerance, or long-term damage, as discussed above.

[0022] Without wishing to be bound by theory, it is believed that the present invention is based on the following principle: skin tissue provides a tight and robust structure, which is believed to enable it to capture, secure, anchor, entangle, and / or retain PBMCs and immunomodulatory agents without allowing them to flow away, thereby providing sufficient prolonged contact between the PBMCs and the immunomodulatory agents while using the subject's body as an in vivo incubator.

[0023] Specifically, the blood supply of the subcutaneous layer, especially the dermis, is primarily provided by capillaries. In contrast to veins and arteries, capillaries have a very narrow cross-sectional area under normal conditions. Only denucleated red blood cells and platelets are compressible and flexible enough to enter and flow through non-dilated capillaries, thereby ensuring the oxygen supply and integrity of the skin. PBMCs are nucleated cells, i.e., contain nuclei. Therefore, PBMCs are too large to fit into non-dilated capillaries. As a result, PBMCs, particularly naive lymphocytes such as naive T cells, are not present in skin capillaries, and thus in the skin, or at least not in effective amounts. In other words, skin tissue normally does not contain or essentially does not contain blood-derived PBMCs, and does not contain blood-derived PBMCs in effective amounts. Therefore, the skin as a whole, including capillaries and tissue, normally contains only a very limited amount of PBMCs, compared to, for example, the vascular system or lymph nodes.

[0024] Therefore, to cause accumulation of PBMCs in the skin, particularly in the skin tissue, PBMCs can be injected, for example, directly into the skin tissue, as in step (A-8), among others.

[0025] Another possible mechanism for PBMC accumulation in the skin involves two factors. First, the PBMC must reach the capillaries and be placed in the vicinity of adjacent skin tissue (e.g., achieved by any of steps (A-1) to (A-7)). This is thought to result in the accumulation of PBMCs in the subject's skin, particularly within the lumen of the skin capillaries. Second, the PBMCs must pass through the capillary wall to leave the capillaries and migrate into the adjacent skin tissue. This migration mechanism is known to occur naturally and does not require any further action or affectation. Briefly, to cross the vascular endothelium of the capillaries, PBMCs, e.g., lymphocytes, begin to bind and roll, come to a complete stop along the interior of the capillary wall, and then pass through the capillary wall, thereby migrating from the capillary lumen to the adjacent skin tissue. Therefore, according to theory, and again without wishing to be bound by theory, apart from administration of PBMCs, for example by injection, also for example any of steps (A-1) to (A-7) below, results in accumulation of PBMCs in the skin, particularly in the lumen of the cutaneous capillaries, and ultimately in the skin tissue due to natural migration of PBMCs out of the capillaries towards the skin tissue.

[0026] After accumulation, i.e., migration and / or administration into skin tissue, PBMCs are thought to be captured and retained by skin tissue, unlike in blood, and cannot be washed away. Similarly, an immunomodulatory substance administered to the skin (e.g., in step (B) and / or (C)) does not wash away and is not diluted by the blood, but remains there for a certain period of time limited by at least its diffusion rate. The simultaneous capture and retention of the immunomodulatory substance and PBMCs allows PBMCs, e.g., lymphocytes, more particularly naive lymphocytes such as naive T cells, to be incubated with the immunomodulatory substance for a sufficient period of time. The PBMCs are thereby incubated in vivo, which can (further) affect the PBMCs, such as regulating, inducing, suppressing, maturing, differentiating, changing, and / or proliferating the PBMCs. The administered immunomodulatory substance may be capable of exerting a desired effect on the PBMCs.

[0027] Furthermore, dendritic cells such as Langerhans cells are naturally present in skin tissue, particularly in the basal part of the epidermis, but they are not present in the blood. Without wishing to be bound by theory again, it is believed that such dendritic cells can also act on PBMCs. Such actions by dendritic cells may be additional to, combined with, enhancing, and / or synergistic with immunomodulatory substances. Therefore, in particular, Langerhans cells may provide an optimal or advantageous microenvironment supporting PBMC affection, but they cannot replace or compensate for the administration of immunomodulatory substances.

[0028] After acting on PBMCs (e.g., naive PBMCs), the acted PBMCs, which are no longer naive, naturally leave the skin, enter the bloodstream, and migrate to their site of action in the subject's body without any further action or function. The site of action may be, for example, an inflamed joint in the subject's body. The effects of the present invention are primarily conferred by the acted PBMCs, particularly regulatory T cells and / or helper T cells or a subset thereof.

[0029] For the reasons stated above, skin is highly suitable for use as an in vivo PBMC incubator, preferably an incubator for naive PBMCs, to generate activated PBMCs such as helper T cells, or subsets thereof, and / or regulatory T cells.

[0030] It can be noted that in addition to acting on PBMCs, immunomodulatory substances can, but do not necessarily, function as attractants, creating a microenvironment that promotes the naturally occurring process of PBMC migration from the capillary lumen across the capillary wall to the surrounding tissue. Nevertheless, this does not replace the fact that PBMCs must accumulate in the dermal capillaries or the dermal capillary lumen prior to passing through the capillary wall. This requires means other than the administration of an immunomodulatory substance and can be achieved, for example, by any of steps (A-1) to (A-7). As already mentioned above, dermal capillaries, in their non-dilated basal state, are too narrow for PBMCs to be forced into and through them. The immunomodulatory substances administered in the present invention do not provide for the presence of PBMCs in the dermal capillaries.

[0031] The present invention provides an immunomodulatory and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: The method comprises, and preferably consists of, step (A), wherein step (A) comprises: (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 in the skin of the subject and / or increasing rHb in the skin of the subject; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method comprises step (B): (B) administering an immunomodulatory agent to the skin of the subject. or preferably further comprising, or further consisting of, or The method comprises, and preferably consists of, step (A), wherein step (A) comprises: (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 in the skin of the subject and / or increasing rHb in the skin of the subject; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method further comprises step (C): (C) administering an immunomodulatory agent to the skin of the subject. or preferably further comprising, or further consisting of, or The method comprises, and preferably consists of, step (A), wherein step (A) comprises: (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 in the skin of the subject and / or increasing rHb in the skin of the subject; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method is selected from one or more of: (B) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). Further comprising, or preferably further consisting of, The present invention relates to immunomodulatory and / or skin conditioning agents, and any of such methods.

[0032] In a preferred aspect of all embodiments of the invention described herein, the invention provides an immunomodulatory substance and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: The method comprises, and preferably consists of, step (A), wherein step (A) comprises: (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 in the skin of the subject and / or increasing rHb in the skin of the subject; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method comprises step (B): (B) administering an immunomodulatory agent to the skin of the subject. or preferably further comprising, or further consisting of, or The method comprises, and preferably consists of, step (A), wherein step (A) comprises: (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 in the skin of the subject and / or increasing rHb in the skin of the subject; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method is selected from one or more of: (B) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). Further comprising, or preferably further consisting of, The present invention relates to immunomodulatory and / or skin conditioning agents, and any of such methods.

[0033] In a more preferred aspect of all embodiments of the invention described herein, the invention provides an immunomodulatory substance and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: The method comprises, and preferably consists of, step (A), wherein step (A) comprises: (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 in the skin of the subject and / or increasing rHb in the skin of the subject; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method is selected from one or more of: (B) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). Further comprising, or preferably further consisting of, The present invention relates to immunomodulatory and / or skin conditioning agents, and any of such methods.

[0034] For purposes of brevity and clarity, several of the following embodiments will generally refer to step (A). However, unless otherwise stated, it should be understood that any of these embodiments independently refer to any of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), and / or (A-8).

[0035] The immunomodulatory substance administered in step (B) may be or may be denoted as the first immunomodulatory substance, the immunomodulatory substance administered in step (C) may be or may be denoted as the second immunomodulatory substance, and the immunomodulatory substance administered in step (B1) (see below) may be or may be denoted as the third immunomodulatory substance. Unless otherwise stated, it should be understood that any embodiment or definition described herein with respect to an immunomodulatory substance can be applied mutatis mutandis independently to the first immunomodulatory substance, second immunomodulatory substance, and third immunomodulatory substance in any of the embodiments described herein, and particularly to any of the medical device embodiments described herein.

[0036] It should be understood that the terms "first," "second," and "third," when referred to in any of the embodiments described herein with respect to immunomodulatory agents, do not intend or imply any order, hierarchy, or priority among the first, second, and third immunomodulatory agents (also referred to as immunomodulatory agents). These terms serve only to uniquely assign, designate, and refer to the corresponding immunomodulatory agents.

[0037] Preferably, the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented in any of the embodiments described herein requires treating and / or preventing an alteration in the subject's immune system, which may be downregulation of the immune system.

[0038] Down-regulation can be, for example, anti-inflammatory regulation and / or less aggressive regulation in the recognition of antigens, autoantigens or antigen-presenting cells, thereby resulting, for example, in reduced inflammatory activity and swelling.

[0039] The inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as mentioned in any of the embodiments described herein are: - requires treatment and / or prevention of downregulation of the immune system, more preferably of the immune system of a subject; and / or - characterized by symptoms caused by an overly aggressive and / or hyperactive immune response in the subject's body; and / or - including overexpression and / or hyperactivity of cytotoxic T cells; and / or - is not caused by the subject's genetic condition; and / or - immunological and / or autoimmune background, More preferably, the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is an immunological disease, an autoimmune disease and / or organ rejection after organ transplantation, even more preferably an immunological and / or autoimmune disease. It can be noted that while an inflammatory disease can have an immunological or autoimmune background, an immunological or autoimmune disease does not necessarily have to involve inflammation; and / or - Inflammation It is preferable.

[0040] More preferably, the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented as mentioned in any of the embodiments described herein is: - arthritis, Preferably, as defined in the preferred embodiments of arthritis described herein; - synovitis and / or tenosynovitis, Preferably according to the code M65.- of the standard ICD-10-GM 2021; - inflammatory rheumatic diseases, Preferably, as defined in the preferred embodiments of the inflammatory rheumatic diseases described herein; - Graves' disease (also known as Graves' disease), Preferably according to the code E05.0 of the standard ICD-10-GM 2021; - Hashimoto's disease (also known as Hashimoto's thyroiditis), Preferably according to code E06.3 of the standard ICD-10-GM 2021; - Including but not limited to multiple sclerosis Preferably according to the code G35.- of the standard ICD-10-GM 2021, more preferably according to the code G35.10 Inflammatory diseases of the nervous system, including: - Crohn's disease (Morbus Crohn), Preferably according to the code K50.- of the standard ICD-10-GM 2021; - anterior uveitis (Uveitis anteriora) and / or iridocyclitis, Preferably according to the codes H20.0, H20.1 and H20.9 of the standard ICD-10-GM 2021; - Diabetic diseases such as type 1 diabetes, Preferably according to the code E10.- of the standard ICD-10-GM 2021; - myasthenia gravis, Preferably according to the code G70.0 of the standard ICD-10-GM 2021; - glomerulonephritis based on an autoimmune background, not caused by a genetic or bacterial background, for example, Preferably according to the code N05.- of the standard ICD-10-GM 2021; - Autoimmune hepatitis, preferably according to the code K75.4 of the ICD-10-GM 2021 standard; and / or Hepatitis C, preferably according to the code B18.2 of the ICD-10-GM 2021 standard Hepatitis, including; - APECED (also known as autoimmune polyendocrine syndrome type 1), Preferably according to the code E31.0 of the standard ICD-10-GM 2021; - Goodpasture's syndrome, Preferably according to the code M31.- of the standard ICD-10-GM 2021; - CIDP (also known as chronic inflammatory demyelinating polyneuropathy), Preferably according to code G61.8 of the standard ICD-10-GM 2021; and / or Guillain-Barré syndrome, Preferably according to the code G61.0 of the standard ICD-10-GM 2021 Polyneuritis (Polyneuritides), preferably according to the code G61.- of the ICD-10-GM 2021 standard; - Lichen mucosae, Preferably according to code L43.- of the standard ICD-10-GM 2021; and / or - Stiff person syndrome, Preferably according to the code G25.88 of the standard ICD-10-GM 2021 It comprises, and preferably consists of,

[0041] The expression "Reference ICD-10-GM 2021", when referred to in any of the embodiments described herein, means "ICD-10-GM 2021 Systematisches Verzeichnis: Internationale statistische Klassifikation der Krankheiten und verwandter Gesundheitsprobleme, 10. Revision - German Modification", Deutscher Arzteverlag, ISBN-13:978-3-7691-3722-4.

[0042] Even more preferably, the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is / are: - arthritis, Preferably, as defined in the preferred embodiments of arthritis described herein; - synovitis and / or tenosynovitis, Preferably according to the code M65.- of the standard ICD-10-GM 2021; - inflammatory rheumatic diseases, Preferably, as defined in the preferred embodiments of the inflammatory rheumatic diseases described herein; - Hashimoto's disease (also known as Hashimoto's thyroiditis), Preferably according to code E06.3 of the standard ICD-10-GM 2021; - Graves' disease (also known as Graves' disease), Preferably according to the code E05.0 of the standard ICD-10-GM 2021; - Crohn's disease, Preferably according to the code K50.- of the standard ICD-10-GM 2021; and / or - Including but not limited to multiple sclerosis Preferably according to the code G35.- of the standard ICD-10-GM 2021, more preferably according to the code G35.10 Inflammatory diseases of the nervous system, including It comprises, and preferably consists of,

[0043] Preferably, arthritis, when referred to in any of the embodiments described herein, comprises, preferably consists of, and more preferably is polyarthritis, monoarthritis, oligoarthritis and / or polyarthritis, preferably according to the standard ICD-10-GM 2021 codes M13.-, M14.-, M15.- and / or M25.-, more preferably code M25.5.

[0044] Preferably, synovitis and / or tenosynovitis, when referred to in any of the embodiments described herein, comprises, preferably consists of, synovitis and tenosynovitis, more preferably synovitis, preferably according to the code M65.- of the standard ICD-10-GM 2021.

[0045] Preferably, the inflammatory rheumatic disease, when referred to in any of the embodiments described herein, is: - Rheumatoid arthritis (RA) (also known as chronic polyarthritis), Preferably according to the code M05.-, more preferably according to the code M05.80 of the standard ICD-10-GM 2021; - Juvenile arthritis, Preferably according to the code M08.- of the standard ICD-10-GM 2021; - Bechterev's disease (also known as ankylosing spondylitis), Preferably according to the code M45.- of the standard ICD-10-GM 2021; psoriatic arthritis, Preferably according to the code M07.- of the standard ICD-10-GM 2021; Enteropathy-associated arthritis (associated with bowel diseases such as ulcerative colitis); Preferably according to the code M07.- of the standard ICD-10-GM 2021; reactive arthritis, Preferably according to the code M02.- of the standard ICD-10-GM 2021; and / or Undifferentiated spondyloarthritis Spondyloarthritides, including spondyloarthritis; - Connective tissue diseases, such as: systemic sclerosis, Preferably according to the code M34.9 of the standard ICD-10-GM 2021; Sjögren's syndrome, Preferably according to the code M35.0 of the standard ICD-10-GM 2021; polymyositis, Preferably according to the code M33.- of the standard ICD-10-GM 2021; dermatomyositis and mixed connective tissue disease, Preferably according to the codes M30 to M36 of the standard ICD-10-GM 2021; and / or lupus erythematosus, Preferably according to the code L93.- of the standard ICD-10-GM 2021; - vasculitis (diseases involving inflammation of blood vessels), Preferably according to the codes L93.-, L95.- or M05.- of the standard ICD-10-GM 2021; - Polymyalgia rheumatica, Preferably according to code M35.3 of the standard ICD-10-GM 2021; - SAPHO syndrome (also known as synovitis-acne-pustulosis-hyperostosis-osteitis syndrome), Preferably according to code M86.3 of the standard ICD-10-GM 2021; - Polychondritis, Preferably according to code M94.1 of the standard ICD-10-GM 2021; - generalized fibromyositis, Preferably according to the code G71.- of the standard ICD-10-GM 2021; - ankylosing spine syndrome, Preferably according to code G71.2 of the standard ICD-10-GM 2021; - Isaacs syndrome, Preferably according to code G71.1 of the standard ICD-10-GM 2021, and / or Morvan's syndrome, Preferably according to the code G60.8 of the standard ICD-10-GM 2021 Neuromyotonia, including and / or - Cramps (Satoyoshi disease), Preferably according to the code M35.8 of the standard ICD-10-GM 2021 It comprises, and preferably consists of,

[0046] More preferably, the inflammatory rheumatic disease is rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica and / or Bechterew's disease, even more preferably rheumatoid arthritis, polymyalgia rheumatica and / or Bechterew's disease.

[0047] More preferably, the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented comprises, preferably consists of, arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease, Graves' disease, Crohn's disease and / or multiple sclerosis, even more preferably arthritis, synovitis, tenosynovitis, rheumatoid arthritis, polymyalgia rheumatica, Bechterew's disease, psoriatic arthritis, Hashimoto's disease, Graves' disease, Crohn's disease and / or multiple sclerosis, and even more preferably polyarthritis, synovitis, rheumatoid arthritis, polymyalgia rheumatica, Bechterew's disease, Graves' disease and / or multiple sclerosis.

[0048] The inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented and any of their preferred embodiments can be defined and / or determined, preferably by any method and / or parameter commonly used in the art and known to the skilled person. Preferably, the definition and / or determination is according to the standard ICD-10-GM 2021, preferably according to the codes of the standard ICD-10-GM 2021 that are indicated as preferred for the inflammatory, immunological and / or autoimmune disease embodiments and their preferred embodiments.

[0049] More preferably, the definition and / or determination of arthritis, even more preferably monoarthritis, oligoarthritis and / or polyarthritis, is according to the reference ICD-10-GM 2021, preferably according to codes M13.-, M14.-, M15.- and / or M25.-, more preferably according to code M25.5 of the reference ICD-10-GM 2021. And even more preferably, the definition and / or determination of polyarthritis is according to the reference ICD-10-GM 2021, preferably according to codes M13.-, M14.-, M15.- and / or M25.-, more preferably according to code M25.5 of the reference ICD-10-GM 2021.

[0050] More preferably, the definition and / or determination of synovitis and / or tenosynovitis according to the standard ICD-10-GM 2021, even more preferably according to code M65.- of the standard ICD-10-GM 2021.

[0051] More preferably, the definition and / or determination of inflammatory rheumatic diseases is in accordance with the criteria ICD-10-GM 2021, which are indicated as being preferred for the embodiments of inflammatory rheumatic diseases and their preferred embodiments.

[0052] Therefore, even more preferably, the definition and / or determination of rheumatoid arthritis is in accordance with the reference ICD-10-GM 2021, preferably in accordance with code M05.-, more preferably in accordance with code M05.80 of the reference ICD-10-GM 2021.

[0053] Even more preferably, the definition and / or determination of polymyalgia rheumatica is in accordance with the standard ICD-10-GM 2021, preferably in accordance with code M35.3 of the standard ICD-10-GM 2021.

[0054] Even more preferably, the definition and / or determination of Bechterev's disease according to the standard ICD-10-GM 2021, preferably according to code M45.- of the standard ICD-10-GM 2021.

[0055] Even more preferably, the definition and / or determination of psoriatic arthritis according to the standard ICD-10-GM 2021, preferably according to the code M07.- of the standard ICD-10-GM 2021.

[0056] More preferably, the definition and / or determination of Graves' disease is in accordance with the standard ICD-10-GM 2021, preferably code E05.0 of the standard ICD-10-GM 2021.

[0057] More preferably, the definition and / or determination of Hashimoto's thyroiditis according to the standard ICD-10-GM 2021, preferably according to code E06.3 of the standard ICD-10-GM 2021.

[0058] More preferably, the definition and / or determination of multiple sclerosis according to the standard ICD-10-GM 2021, preferably according to code G35.-, more preferably according to code G35.10 of the standard ICD-10-GM 2021.

[0059] The subject as referred to in any of the embodiments described herein may be, and preferably is, any subject in need of treatment and / or prevention.

[0060] A subject, as referred to in any of the embodiments described herein, can be, and preferably is, any subject having an immune system capable of generating an adaptive immune response, preferably capable of generating a T cell immune response.

[0061] Preferably, the subject is a vertebrate, more preferably a mammal, even more preferably a human or any of a mammalian genus and / or species selected from cow, buffalo, horse, donkey, elephant, sheep, goat, pig, rabbit, mouse, rat, camel, dromedary, llama, alpaca, dog and / or cat. Also more preferably, the subject is a human.

[0062] A subject, as referred to in any of the embodiments described herein, can be, and preferably is, a neonate, infant, toddler, child, adolescent, and / or adult subject, preferably an infant, toddler, child, adolescent, and / or adult, and more preferably an infant, child, adolescent, or adult, and more preferably a child, adolescent, and / or adult, and even more preferably an adolescent and / or adult, and even more preferably an adult. When the subject is a human, a neonate is up to 28 days old, an infant is from the beginning of 29 days old to the end of 12 months old, a toddler is from the beginning of 13 months old to 3 years old, a child is from the beginning of 4 years old to 12 years old, an adolescent is from the beginning of 13 years old to 18 years old, and an adult is from the beginning of 19 years old.

[0063] Preferably, the subject is one who has been diagnosed with an inflammatory, immunological and / or autoimmune disease and / or is shown to be at risk for developing an inflammatory, immunological and / or autoimmune disease.

[0064] Preferably, the subject who has been diagnosed with an inflammatory, immunological and / or autoimmune disease is a subject who has been diagnosed with arthritis, synovitis, tenosynovitis, inflammatory rheumatic disease, Hashimoto's disease, Graves' disease and / or multiple sclerosis, even more preferably arthritis, synovitis, tenosynovitis, rheumatoid arthritis, polymyalgia rheumatica, Bechterew's disease, psoriatic arthritis, Hashimoto's disease, Graves' disease and / or multiple sclerosis, and even more preferably polyarthritis, synovitis, rheumatoid arthritis, polymyalgia rheumatica, Bechterew's disease, Graves' disease and / or multiple sclerosis.

[0065] Preferably, the subject indicated to be at risk of developing an inflammatory, immunological and / or autoimmune disease is a subject indicated to be at risk of developing arthritis, synovitis, tenosynovitis, inflammatory rheumatic disease, Hashimoto's disease, Graves' disease and / or multiple sclerosis, even more preferably arthritis, synovitis, tenosynovitis, rheumatoid arthritis, polymyalgia rheumatica, Bechterew's disease, psoriatic arthritis, Hashimoto's disease, Graves' disease and / or multiple sclerosis, and even more preferably polyarthritis, synovitis, rheumatoid arthritis, polymyalgia rheumatica, Bechterew's disease, Graves' disease and / or multiple sclerosis.

[0066] Typically, in a subject who has been diagnosed with an inflammatory, immunological, and / or autoimmune disease, symptoms of the inflammatory, immunological, and / or autoimmune disease are already evident and the subject is afflicted with the symptoms of the inflammatory, immunological, and / or autoimmune disease, in other words, the inflammatory, immunological, and / or autoimmune disease has already manifested in the subject.

[0067] Usually, in a subject that is shown to have a risk of developing inflammatory disease, immunological disease, and / or autoimmune disease, the symptoms of inflammatory disease, immunological disease, and / or autoimmune disease are not yet evident, and the subject has not yet suffered from the symptoms of inflammatory disease, immunological disease, and / or autoimmune disease.In other words, inflammatory disease, immunological disease, and / or autoimmune disease has not yet appeared in the subject.Having a risk should be understood as meaning that the subject will develop, and / or will have a high probability of developing, inflammatory disease, immunological disease, and / or autoimmune disease.This may indicate, for example, that the subject has a risk of developing Bechterew's disease, rheumatoid arthritis, Crohn's disease, reactive arthritis, or juvenile arthritis, for example, HLA-B. * This may be the case for subjects who carry the 27 allele, or for example, in a family history of subjects in which rheumatoid arthritis has frequently occurred.

[0068] The diagnosis of a subject diagnosed with an inflammatory, immunological and / or autoimmune disease, as referred to in any of the embodiments described herein, can be, and preferably is, established by any method and / or parameter commonly used in the art and known to those skilled in the art, preferably according to the standard ICD-10-GM 2021, preferably according to the codes of the standard ICD-10-GM 2021 that are indicated as preferred for the inflammatory, immunological and / or autoimmune disease embodiments and preferred embodiments thereof.

[0069] More preferably, the diagnosis of the subject being diagnosed with arthritis, even more preferably monoarthritis, oligoarthritis and / or polyarthritis, is established according to the reference ICD-10-GM 2021, preferably according to codes M13.-, M14.-, M15.- and / or M25.-, more preferably according to code M25.5 of the reference ICD-10-GM 2021. Even more preferably, the diagnosis of the subject being diagnosed with polyarthritis, is established according to the reference ICD-10-GM 2021, preferably according to codes M13.-, M14.-, M15.- and / or M25.-, more preferably according to code M25.5 of the reference ICD-10-GM 2021.

[0070] More preferably, the diagnosis of the subject being diagnosed with synovitis and tenosynovitis is established according to the standard ICD-10-GM 2021, even more preferably according to code M65.- of the standard ICD-10-GM 2021.

[0071] More preferably, the diagnosis of the subject who has been diagnosed with an inflammatory rheumatic disease is established according to the criteria ICD-10-GM 2021, which are indicated as being preferred for the inflammatory rheumatic disease embodiment and its preferred embodiments.

[0072] Therefore, even more preferably, the diagnosis of the subject being diagnosed with rheumatoid arthritis is established according to the reference ICD-10-GM 2021, preferably according to M05.-, more preferably according to M05.80 according to the reference ICD-10-GM 2021.

[0073] Even more preferably, the diagnosis of the subject who has been diagnosed with polymyalgia rheumatica is established according to the norm ICD-10-GM 2021, preferably according to M35.3 according to the norm ICD-10-GM 2021.

[0074] Even more preferably, the diagnosis of the subject being diagnosed with Bechterew's disease is established according to the standard ICD-10-GM 2021, preferably according to M45.- according to the standard ICD-10-GM 2021.

[0075] Even more preferably, the diagnosis of the subject being diagnosed with psoriatic arthritis is established according to the standard ICD-10-GM 2021, preferably according to code M07.- of the standard ICD-10-GM 2021.

[0076] More preferably, the diagnosis of the subject who has been diagnosed with Graves' disease is established according to the standard ICD-10-GM 2021, preferably M45.- according to the standard ICD-10-GM 2021.

[0077] More preferably, the diagnosis of the subject being diagnosed with Hashimoto's thyroiditis is established according to the standard ICD-10-GM 2021, preferably M45.- according to the standard ICD-10-GM 2021.

[0078] More preferably, the diagnosis of the subject being diagnosed with multiple sclerosis is established according to the standard ICD-10-GM 2021, preferably M45.- according to the standard ICD-10-GM 2021.

[0079] The indication of a subject indicated to be at risk for developing an inflammatory, immunological and / or autoimmune disease, as referred to in any of the embodiments described herein, can be, and preferably is, established by any method and / or parameter commonly used in the art and known to those skilled in the art. More preferably, the indication is established according to the standard ICD-10-GM 2021.

[0080] Indications of a subject at risk for developing an inflammatory, immunological and / or autoimmune disease can be determined using any method and / or parameter commonly used in the art and known to those skilled in the art, such as, for example, family history and / or HLA-B in the case of Bechterew's disease, rheumatoid arthritis, Crohn's disease, reactive arthritis or juvenile arthritis. * 27, and preferably established by genetic association.

[0081] Preferably, the subject shown to be at risk of developing an inflammatory, immunological and / or autoimmune disease is a subject shown to develop arthritis, monoarthritis, oligoarthritis, polyarthritis and / or any of the inflammatory rheumatic diseases listed above.

[0082] Preferably, the phrase "treating", as referred to in any of the embodiments described herein, means a subject diagnosed with an inflammatory, immunological and / or autoimmune disease and the subject's condition is improved, e.g., pain and / or inflammation is reduced or eliminated; organ, tissue and / or joint destruction is prevented; blood parameters are improved or normalized; further progression of organ, tissue and / or joint destruction is slowed, stopped, and / or regeneration occurs; organ, tissue and / or joint functional capacity is preserved or improved; joint swelling and / or pressure sensitivity is reduced; the subject's normal lifestyle is maintained; and / or the subject's quality of life and / or mental and / or physical well-being is maintained or improved.

[0083] Preferably, the expression "preventing", when referred to in any of the embodiments described herein, means maintaining the health of subjects and subjects diagnosed as being at risk of developing an inflammatory, immunological and / or autoimmune disease, and preventing and / or delaying the onset of symptoms of an inflammatory, immunological and / or autoimmune disease in a subject; preventing organ, tissue and / or joint destruction; preserving organ, tissue and / or joint functional capacity; maintaining a normal lifestyle in a subject; and / or maintaining or improving a subject's quality of life and / or mental and / or physical well-being.

[0084] The expression "PBMCs" ("peripheral blood mononuclear cells"), when referred to in any of the embodiments described herein, typically refers to a subpopulation of cells of the cellular blood components, particularly white blood cells. Preferably, white blood cells comprise, and more preferably consist of, lymphocytes and monocytes as cellular components. Preferably, PBMCs comprise, and more preferably consist of, lymphocytes and monocytes as cellular components, while red blood cells and platelets (which do not possess nuclei) and granulocytes (which possess segmented nuclei) are absent or essentially absent or absent in effective amounts, more preferably absent. More preferably, PBMCs, when referred to in any of the embodiments described herein, are lymphocytes such as natural killer cells, B cells and / or T cells, more preferably B cells and / or T cells, and even more preferably naive PBMCs, also more preferably naive lymphocytes, also even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0085] Preferably, PBMCs, when referred to in any of the embodiments described herein, are blood-derived PBMCs. This applies equally to PBMCs administered, e.g., injected (as may be the case in step (A-8)), as well as any accumulated PBMCs or PBMCs to be accumulated. Therefore, the expression "PBMCs" preferably does not refer to PBMCs that are originally resident in tissue, preferably in skin. Therefore, PBMCs that are originally resident in skin, particularly skin tissue, are preferably not included in accumulated PBMCs, accumulated PBMCs, or PBMCs to be accumulated.

[0086] PBMCs can be extracted from blood, preferably whole blood, and then present in an isolated, preferably purified, form, hereinafter referred to as "isolated PBMCs," or as a subpopulation of cells of cellular blood components within blood, preferably whole blood, hereinafter referred to as "blood PBMCs." In isolated PBMCs, blood components and cellular blood components other than PBMCs are preferably absent in effective amounts, or essentially absent or absent, more preferably absent. Isolated PBMCs can be obtained by any method known to those skilled in the art, preferably by Ficoll extraction combined with gradient centrifugation, or by apheresis, preferably apheresis using whole blood, preferably as described in the Materials and Methods section "Preparation of PBMCs."

[0087] The expression "lymphocytes," when referred to in any of the embodiments described herein, typically refers to a subpopulation of cells of PBMCs. Here, too, lymphocytes can include subpopulations of cells, including B cells, T cells, and / or natural killer cells. Preferably, lymphocytes can comprise, and preferably consist of, B cells, including naive and activated B cells, such as mature B cells; natural killer cells; and / or T cells, including naive and activated T cells, such as mature T cells, as their cellular component. More preferably, lymphocytes, when referred to in any of the embodiments described herein, comprise, and more preferably consist of, naive lymphocytes, activated lymphocytes, and / or natural killer cells, even more preferably naive lymphocytes, and even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells, as their cellular component. Preferably, when referred to in any of the embodiments described herein, lymphocytes are naive lymphocytes, more preferably comprising, and even more preferably consisting of, naive B cells and / or naive T cells as their cellular component. Even more preferably, the lymphocytes are naive T cells.

[0088] The expression "naive" or "naive cells," when referred to in any of the embodiments described herein with respect to any type of cell, such as naive PBMCs, naive lymphocytes, naive B cells, and / or naive T cells, typically have not been exposed to their corresponding antigen. Preferably, such naive cells have not been activated and / or have the potential to be acted upon by an immunomodulatory substance and optionally dendritic cells, more preferably both. Upon actuation, the naive cells become acted upon cells. Even more preferably, the naive cells have not been activated, have the potential to be acted upon, and have not been exposed to their corresponding antigen. Typically, the expression "naive" does not exclude that naive cells have already acquired a degree of regulation, induction, suppression, maturation, differentiation, transformation, and / or proliferation, preferably so long as such cells still have the potential to be acted upon by an immunomodulatory substance and optionally dendritic cells with at least one member of a list of possible effects, such as attraction, regulation, induction, suppression, maturation, differentiation, transformation, and / or proliferation.

[0089] The expression "potential to be affected", when referred to in any of the embodiments described herein with respect to any type of cell, such as naive PBMCs, naive lymphocytes, naive B cells and / or naive T cells, typically means that such naive cells are attracted, regulated, induced, suppressed, matured, differentiated, changed and / or proliferated, more preferably attracted, matured, differentiated and / or proliferated, even more preferably matured, differentiated and / or proliferated, upon action caused by the immunomodulatory substance and optionally dendritic cells.

[0090] The phrase "affected" or "affected cells," when referred to in any of the embodiments described herein with respect to any type of cell, such as affected PBMCs, affected lymphocytes, affected B cells, and / or affected T cells, typically means that such affected cells have undergone attraction, modulation, induction, suppression, maturation, differentiation, change, and / or proliferation, more preferably, attraction, maturation, differentiation, and / or proliferation, even more preferably, maturation, differentiation, and / or proliferation, due to an effect caused by the immunomodulatory substance and optionally dendritic cells. Preferably, "affected" excludes that such affected cells have undergone activation due to an effect caused by the immunomodulatory substance and optionally dendritic cells, i.e., such affected cells do not provide increased aggressiveness against antigens, autoantigens, and / or antigen-presenting cells.

[0091] The expressions "attract," "attracting," "attracted," and / or "attraction," when used in any of the embodiments described herein with reference to any type of cell, such as PBMCs, lymphocytes, B cells, and / or T cells, particularly naive PBMCs, naive lymphocytes, naive B cells, and / or naive T cells, typically mean that such cells are caused to migrate directionally toward an attractant. Such an attractant can be, but is not necessarily, an immunomodulatory substance, for example. For example, the expression means that such cells are caused to leave the lumen of skin capillaries by crossing the vascular endothelium and enter the surrounding skin tissue toward the site where the immunomodulatory substance is present. As already described in more detail above, this migration mechanism is known to occur naturally and does not require any further action or function. Nevertheless, such attractants can promote or contribute to such migration by providing a beneficial microenvironment. Thus, the function can be, but is not necessarily, an attraction, among others. This may be advantageous, for example, in the case of steps (A-0) to (A-7), in which PBMC accumulation occurs (step (A-0)) or is thought to occur (steps (A-1) to (A-7)), particularly within the lumen of skin capillaries. Subsequent passage of PBMCs through the capillary walls depends on naturally occurring processes and ultimately results in, or is thought to result in, accumulation within the skin, particularly within skin tissue. Conversely, for example, in the case of step (A-8), PBMCs can be administered by injection, and PBMC accumulation has already occurred within the skin, particularly within skin tissue. Therefore, migration to skin tissue is not necessary. However, in either case, the accumulated PBMCs and the administered immunomodulatory substance can be captured and retained within the skin, providing in vivo incubation of the PBMCs with the immunomodulatory substance, which may ultimately, in addition to being attracted, become (preferably, modulate, induce, suppress, mature, differentiate, alter, and / or proliferate) affected PBMCs.

[0092] The expressions "proliferate," "proliferating," "proliferated," and / or "proliferation," when referred to in any of the embodiments described herein with respect to any type of cell, typically mean that the amount of such cells is increased / increased or decreased / decreased, preferably increased / increased, compared to the amount of such cells prior to the action caused by the immunomodulatory substance and, optionally, dendritic cells (it may be noted that, depending on the type of cell, a certain amount of such cells may already be present prior to the action due to naturally occurring immune processes in the subject's body). For example, when regulatory T cells and / or helper T cells, or a subset thereof, proliferate, this means that the amount of such cells, preferably in the subject's blood, is increased compared to the amount prior to the action (it may be noted that a certain amount of such cells may already be present prior to the action due to naturally occurring immune processes in the subject's body).

[0093] The expressions "differentiate," "differentiating," "differentiated," and / or "differentiation," when referred to in any of the embodiments described herein with respect to any type of cell, typically mean that such cells may already be differentiated to some extent and have the potential to further differentiate and / or mature.

[0094] The expressions "mature," "maturing," "matured," and / or "mature," when referred to in any of the embodiments described herein with respect to any type of cell, typically mean that such cell does not have the potential to further differentiate and / or mature.

[0095] A differentiated cell can be, for example, a helper T cell, or a subset thereof, that has the potential to mature, for example, into a regulatory T cell. A mature cell can be, for example, a regulatory T cell that no longer has the potential for further differentiation and / or maturation.

[0096] The expression "naive PBMCs", when referred to in any of the embodiments described herein, typically means PBMCs that have, at least to some extent, differentiated.

[0097] Preferably, naive PBMCs, as referred to in any of the embodiments described herein, have never been exposed to their corresponding antigen.

[0098] Preferably, the naive PBMCs have not been activated and / or have the potential to be acted upon by an immunomodulatory agent and optionally dendritic cells, more preferably both, upon actuation, the naive PBMCs become acted upon PBMCs.

[0099] Even more preferably, naive PBMCs are not activated, have the potential to be acted upon, and have not been exposed to their corresponding antigen.

[0100] Preferably, all PBMCs, more preferably all lymphocytes, leaving a pivotal lymphoid organ such as the thymus or bone marrow are considered to be naive PBMCs, more preferably those leaving the bone marrow are naive B lymphocytes, also referred to as naive B cells, and / or those leaving the thymus are naive T lymphocytes, also referred to as naive T cells.

[0101] Naive PBMCs, as referred to in any of the embodiments described herein, more preferably comprise, and even more preferably consist of, as a cellular component, naive lymphocytes, even more preferably naive T cells and / or naive B cells, and also more preferably naive T cells.

[0102] The expression "affected PBMCs," when referred to in any of the embodiments described herein, typically refers to naive PBMCs that have been subjected to an action caused by an immunomodulatory substance and, optionally, dendritic cells. Without wishing to be bound by theory, affected PBMCs are believed to preferably comprise, and more preferably consist of, as cellular components, affected lymphocytes, even more preferably affected B cells and / or affected T cells, also more preferably affected T cells, regulatory B cells, helper T cells or a subset thereof, and / or regulatory T cells; even more preferably regulatory B cells, helper T cells or a subset thereof, and / or regulatory T cells; also more preferably helper T cells or a subset thereof, and / or regulatory T cells. Furthermore, without wishing to be bound by theory, preferably the acted upon PBMCs have undergone attraction, modulation, induction, suppression, maturation, differentiation, alteration and / or proliferation, more preferably attraction, maturation, differentiation and / or proliferation, even more preferably maturation, differentiation and / or proliferation, due to the effects caused by the immunomodulatory substance and optionally dendritic cells. Preferably, the expression "acted upon PBMCs" excludes that the acted upon PBMCs have undergone activation due to the effects caused by the immunomodulatory substance and optionally dendritic cells. Thus, preferably, the acted upon PBMCs do not exhibit increased aggressiveness towards antigens, autoantigens and / or antigen-presenting cells.

[0103] The expression "naive lymphocyte," when referred to in any of the embodiments described herein, typically means a lymphocyte that has, at least to some extent, differentiated.

[0104] Preferably, naive lymphocytes, as referred to in any of the embodiments described herein, have never been exposed to their corresponding antigen.

[0105] Preferably, the naive lymphocytes have not been activated and / or have the potential to be acted upon by an immunomodulatory agent and optionally dendritic cells, more preferably both, upon actuation, the naive lymphocytes become acted upon lymphocytes.

[0106] Even more preferably, naive lymphocytes are those that have not been activated, have the potential to be acted upon, and have not been exposed to their corresponding antigen.

[0107] Preferably, all lymphocytes leaving pivotal lymphoid organs such as the thymus or bone marrow are considered to be naive lymphocytes. More preferably, those leaving the bone marrow are naive B lymphocytes, also called naive B cells, and / or those leaving the thymus are naive T lymphocytes, also called naive T cells.

[0108] Naive lymphocytes, when referred to in any of the embodiments described herein, more preferably comprise, and even more preferably consist of, naive T cells and / or naive B cells, and more preferably naive T cells, as a cellular component.

[0109] The expression "affected lymphocytes," when referred to in any of the embodiments described herein, typically refers to naive lymphocytes that have been affected by an immunomodulatory substance and, optionally, dendritic cells. Without wishing to be bound by theory, it is believed that affected lymphocytes preferably comprise, and more preferably consist of, memory B cells, plasma cells, regulatory B cells, helper T cells or a subset thereof, and / or regulatory T cells as cellular components; more preferably, regulatory B cells, helper T cells or a subset thereof, and / or regulatory T cells; even more preferably, helper T cells or a subset thereof, and / or regulatory T cells. Furthermore, without wishing to be bound by theory, it is preferred that affected lymphocytes have undergone attraction, regulation, induction, suppression, maturation, differentiation, change, and / or proliferation, more preferably, attraction, maturation, differentiation, and / or proliferation, and even more preferably, maturation, differentiation, and / or proliferation, due to the effect caused by the immunomodulatory substance and, optionally, dendritic cells. Preferably, the expression "affected lymphocytes" excludes that the affected lymphocytes have undergone activation due to effects caused by immunomodulatory substances and, optionally, dendritic cells. Preferably, therefore, the affected lymphocytes do not exhibit increased aggressiveness towards antigens, autoantigens and / or antigen-presenting cells.

[0110] The expression "naive T cells," as referred to in any of the embodiments described herein, typically refers to T cells that have differentiated, preferably at least to some extent, in the thymus and have successfully undergone the positive and negative processes of central selection in the thymus. Furthermore, naive T cells can be or have been released by the thymus.

[0111] Preferably, naive T cells, as referred to in any of the embodiments described herein, have never been exposed to their corresponding antigen.

[0112] Preferably, the naive T cells are not activated and / or have the potential to be acted upon by an immunomodulatory agent and optionally dendritic cells, more preferably both, and upon actuation, the naive T cells become acted upon T cells.

[0113] Even more preferably, naive T cells are not activated, have the potential to be acted upon, and have not been exposed to their corresponding antigen.

[0114] The expression "affected T cells," when referred to in any of the embodiments described herein, typically refers to naive T cells that have been subjected to an effect caused by an immunomodulatory substance and, optionally, dendritic cells. Without wishing to be bound by theory, it is believed that affected T cells preferably comprise, and more preferably consist of, helper T cells and / or regulatory T cells as cellular components; more preferably, helper T cells and / or regulatory T cells. Furthermore, without wishing to be bound by theory, it is preferred that affected T cells have undergone attraction, modulation, induction, suppression, maturation, differentiation, transformation, and / or proliferation, more preferably, attraction, maturation, differentiation, and / or proliferation, and even more preferably, maturation, differentiation, and / or proliferation, due to an effect caused by the immunomodulatory substance and, optionally, dendritic cells. Preferably, the expression "affected T cells" excludes that affected T cells have undergone activation not specifically caused by an effect caused by the immunomodulatory substance and, optionally, dendritic cells. Therefore, preferably, the affected T cells do not provide increased aggressiveness against antigens, autoantigens and / or antigen presenting cells.

[0115] According to the above definitions of naive T cells and stimulated T cells, it can be pointed out that helper T cells can be considered as naive T cells and / or stimulated T cells.

[0116] The expression "naive B cells," when referred to in any of the embodiments described herein, means B cells that have differentiated, at least to some extent, typically in the bone marrow.

[0117] Preferably, naive B cells, as referred to in any of the embodiments described herein, have never been exposed to their corresponding antigen.

[0118] Preferably, the naive B cells are not activated and / or have the potential to be acted upon by an immunomodulatory agent and optionally a dendritic cell, more preferably both, and upon actuation, the naive B cells become acted upon B cells.

[0119] Even more preferably, naive B cells are not activated, have the potential to be acted upon, and have not been exposed to their corresponding antigen.

[0120] The expression "affected B cells," when referred to in any of the embodiments described herein, typically refers to naive B cells that have been affected by an immunomodulatory substance and, optionally, dendritic cells. Without wishing to be bound by theory, it is believed that affected B cells preferably comprise, and more preferably consist of, memory B cells, plasma cells, and / or regulatory B cells as cellular components; even more preferably, regulatory B cells. Preferably, affected B cells have undergone attraction, modulation, induction, suppression, maturation, differentiation, transformation, and / or proliferation, more preferably, attraction, maturation, differentiation, and / or proliferation, and even more preferably, maturation, differentiation, and / or proliferation, due to the effect caused by the immunomodulatory substance and, optionally, dendritic cells. Preferably, the expression "affected B cells" excludes that affected B cells have undergone activation due to the effect caused by the immunomodulatory substance and, optionally, dendritic cells. Therefore, preferably, affected B cells do not exhibit increased aggressiveness against antigens, autoantigens, and / or antigen-presenting cells.

[0121] Unless otherwise stated, the definitions of PBMC, naive PBMC, affected PBMC, lymphocyte, naive lymphocyte, affected lymphocyte, T cell, naive T cell, affected T cell, helper T cell or subset thereof, B cell, naive B cell, affected B cell and preferred embodiments thereof apply broadly to any of the embodiments as described herein in which PBMC, naive PBMC, affected PBMC, lymphocyte, naive lymphocyte, affected lymphocyte, T cell, naive T cell, affected T cell, helper T cell or subset thereof, B cell, naive B cell and / or affected B cell are referenced.

[0122] Unless otherwise stated, it should be understood that any embodiment or definition of an immunomodulatory substance as described herein is independently applicable mutatis mutandis to the immunomodulatory substance as referred to in any of the embodiments described herein, in particular to the immunomodulatory substance for use in accordance with the invention, step (B), (B1) and / or step (C), pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit.

[0123] The expression "immunomodulatory substance" or "immunomodulatory substances" when referred to in any of the embodiments described herein, in particular immunomodulatory substances for use in accordance with the invention and / or immunomodulatory substances of steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits, may be, and preferably is, any type of substance that is capable of and / or does act, preferably directly and / or indirectly, on PBMCs.

[0124] The phrase "act" or "acting," when referred to in any of the embodiments described herein with respect to immunomodulatory substances and in any of their preferred embodiments, typically means that the immunomodulatory substance attracts, modulates, induces, suppresses, matures, differentiates, alters, and / or proliferates PBMCs, more preferably attracts, matures, differentiates, and / or proliferates PBMCs, and even more preferably matures, differentiates, and / or proliferates PBMCs (in other words, the immunomodulatory substance attracts, modulates, induces, alters, and / or suppresses PBMCs and / or causes PBMCs to mature, differentiate, and / or proliferate). Preferably, "act" or "acting" excludes the immunomodulatory substance activating PBMCs. Thus, preferably, upon actin, the acted PBMCs do not provide increased aggressiveness against antigens, autoantigens, and / or antigen-presenting cells. More preferably, the PBMCs are naive PBMCs, even more preferably lymphocytes, also more preferably T cells and / or B cells, also even more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, even more preferably naive T cells.

[0125] The phrase "capable of acting," when referred to in any of the embodiments described herein with respect to immunomodulatory substances and in any of their preferred embodiments, typically means that the immunomodulatory substance is capable of attracting, regulating, inducing, suppressing, maturing, differentiating, altering, and / or expanding PBMCs, more preferably attracting, maturing, differentiating, and / or expanding PBMCs, and even more preferably, maturing, differentiating, and / or expanding PBMCs. Preferably, "capable of acting" excludes that the immunomodulatory substance is capable of activating PBMCs. Thus, preferably, upon potential action, the acted PBMCs do not provide increased aggressiveness against antigens, autoantigens, and / or antigen-presenting cells. More preferably, the PBMCs are naive PBMCs, even more preferably lymphocytes, also more preferably T cells and / or B cells, still more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0126] Thus, more preferably, the immunomodulatory substance is capable of and / or acts on PBMCs by attracting, proliferating, differentiating, and / or maturing, even more preferably by proliferating, differentiating, and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the immunomodulatory substance is capable of and / or causes PBMCs to attract, proliferate, differentiate, and / or mature. Even more preferably, the immunomodulatory substance is capable of and / or causes PBMCs to proliferate, differentiate, and / or mature. Even more preferably, the immunomodulatory substance is capable of and / or causes PBMCs to differentiate and / or mature. More preferably, the PBMCs are naive PBMCs, even more preferably lymphocytes, also more preferably T cells and / or B cells, even more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0127] The expression "directly," when referred to in any of the embodiments described herein, typically in the context of "acting on" or "capable of acting on" PBMCs, means that the immunomodulatory substance itself functions or is capable of functioning as an effector that causes the desired action of the PBMCs. For example, it is capable of activating or may be capable of activating a respective receptor of the immunomodulatory substance on the cell. The receptor of the immunomodulatory substance may be, for example, that of the PBMC. For example, if the immunomodulatory substance is a cytokine, the cytokine may be capable of activating a respective cytokine receptor. More preferably, the PBMCs are naive PBMCs, even more preferably lymphocytes, also more preferably T cells and / or B cells, still more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, even more preferably naive T cells.

[0128] The expression "indirectly," when referred to in any of the embodiments described herein, typically means that the immunomodulatory substance is any substance that causes or induces, or is capable of causing or inducing, the production of an immunomodulatory substance, particularly a precursor, propeptide, or prodrug. In other words, immunomodulatory substances can encompass substances that are not normally active in themselves, i.e., do not have immunomodulatory activity, such as action or ability to act, but that are actually converted into an active immunomodulatory substance when used in accordance with the present invention. Thereby, the desired action on PBMCs is achieved indirectly. This can be, for example, when the immunomodulatory substance is any substance, such as: - an inducer that induces cells to produce and / or secrete immunomodulatory substances, and such cells may be any cells capable of producing and / or secreting immunomodulatory substances, such as PBMCs or any subpopulation of cells of PBMCs or any cells other than PBMCs, preferably dendritic cells, more preferably skin-resident dendritic cells such as Langerhans cells; - precursors of immunomodulatory agents, e.g., precursors of immunomodulatory agents that are metabolized by the body of a subject to produce immunomodulatory agents, including, for example, peptides, proteins, protein analogs, protein variants, propeptides, derivatives thereof, RNA, DNA, salts, capped immunomodulatory agents, etc., among others; - inhibitors of substances, such as particles or nanoparticles or cap structures, enzymes or factors that prevent the expression, interaction, production, secretion and / or activity of immunomodulatory substances. The immunomodulatory substances can, for example, be loaded into particles for delivery. These particles can sterically prevent and protect the substance from interacting with its target, e.g., receptor, and the substance can only exert its function after release from the particle, e.g., in the patient's body; - prodrugs of immunomodulatory substances; - immunomodulatory muteins; - Biopharmaceuticals, such as immunomodulatory biologics, biosimilars, biomimetic, biobetters and / or biosuperiors; and / or - Codrugs of immunomodulatory substances.

[0129] More preferably, the PBMCs to be acted upon are naive PBMCs, even more preferably lymphocytes, still more preferably T cells and / or B cells, still more preferably naive lymphocytes, still more preferably naive B cells and / or naive T cells, still more preferably naive T cells; etc.

[0130] The expression "biopharmaceutical" encompasses biologics, biosimilars, biomimetics, biobetters and / or biosuperiors.

[0131] More preferably, the immunomodulatory substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is: - capable of and / or acts, preferably directly and / or indirectly, on PBMCs in the subject, more preferably in the skin of the subject; - is capable of and / or acts, preferably directly and / or indirectly, on PBMCs in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably in a subject as defined in any of the embodiments according to the present invention, more preferably in the skin of a vertebrate, even more preferably in the skin of a mammal, again more preferably in the skin of a human or a mammal as defined above, even more preferably in the skin of a subject; - capable of and / or acts, preferably directly and / or indirectly, on PBMCs in the skin of the subject; - capable of acting directly on PBMCs and / or acts directly on PBMCs; and / or - be capable of and / or act on PBMCs by attracting, proliferating, differentiating and / or maturing, even more preferably by proliferating, differentiating and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the immunomodulatory substance is capable of and / or causes PBMCs to attract, proliferate, differentiate and / or mature. Even more preferably, the immunomodulatory substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the immunomodulatory substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the immunomodulatory substance is capable of and / or causes PBMCs to differentiate and / or mature. Preferably, the PBMCs are naive PBMCs, more preferably lymphocytes, even more preferably T cells and / or B cells, also more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, even more preferably naive T cells.

[0132] Even more preferably, the immunomodulatory substance is capable of and / or causes the direct and / or indirect proliferation, differentiation and / or maturation of naive T cells in a subject, more preferably in the skin of a subject, as defined in any of the embodiments in accordance with the present invention. Even more preferably, the immunomodulatory substance is capable of and / or causes the direct proliferation, differentiation and / or maturation of naive T cells in a subject, more preferably in the skin of a subject, as defined in any of the embodiments in accordance with the present invention.

[0133] Preferably, the immunomodulatory substance referred to in any of the embodiments described herein, particularly the immunomodulatory substance for use in accordance with the present invention and / or steps (B), (B1), and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device, and / or kit, can include precursors, prodrugs, and propeptides of such substances that are not normally active, i.e., do not have immunomodulatory activity, but are converted into an active immunomodulatory substance upon use in accordance with the present invention. Thus, preferably, the immunomodulatory substance is any substance, molecule, peptide, protein, protein analog, protein variant, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, propeptide, and / or any derivative, fragment, or pharmaceutically acceptable salt of any of these. More preferably, the immunomodulatory substance is any peptide, protein, protein analog, protein variant, inducer, precursor, prodrug, mutein, codrug, and / or any derivative, fragment, or pharmaceutically acceptable salt of any of these.

[0134] The interferon-like functional immunomodulatory substance can be any naturally occurring or artificial immunomodulatory substance, so long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and is capable of activating particular interferon receptors.

[0135] More preferably, the immunomodulatory substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the invention and / or the immunomodulatory substance of steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits, is any peptide, protein and / or derivative or fragment of any of these that may be similar or identical to, preferably similar or identical to, and more preferably identical to, any peptide, protein or fragment of any of these that naturally occurs in a vertebrate, preferably a human or mammal as defined above, more preferably in a subject as defined in any of the embodiments in accordance with the invention.

[0136] Even more preferably, the immunomodulatory agent has 70% or more, more preferably 85% or more, even more preferably 90% or more, even more preferably 95% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more and 100% or less amino acid sequence identity to any peptide, protein, or fragment of any thereof, naturally occurring in a vertebrate, preferably a mammal, more preferably a human or mammal as defined above, and even more preferably a subject as defined in any of the embodiments according to the present invention. Preferably, the amino acid sequence identity includes amino acid residue substitutions, insertions, and / or deletions relative to the naturally occurring peptide, protein, or fragment of any thereof. Preferably, the total number of amino acid substitutions, insertions, and / or deletions, or the total number of substitutions, insertions, and / or deletions combined, is 60 or less, more preferably 40 or less, even more preferably 20 or less, even more preferably 12 or less, even more preferably 8 or less, even more preferably 4 or less, even more preferably 2 or less and zero or more, and even more preferably zero.

[0137] Also more preferably, the immunomodulatory agent is identical, or refers to amino acid sequence identity, to an endogenous immunomodulatory agent of the same genus and / or species to which the subject belongs. The expression "identical" typically means in this particular context that the immunomodulatory agent is identical, with respect to its primary, secondary, tertiary, and quaternary protein structure, and more preferably also taking into account modification patterns, particularly glycosylation, to an immunomodulatory agent of the same genus and / or species to which the subject belongs.

[0138] Preferably, the immunomodulatory substance, as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits, is derived from an individual belonging to the same genus and / or species as the subject, or is identical to the immunomodulatory substance of the same genus and / or species to which the subject belongs. For example, if the subject is a human, the immunomodulatory agent is a human immunomodulatory agent; if the subject is a cow, the immunomodulatory agent is a bovine immunomodulatory agent; if the subject is a horse, the immunomodulatory agent is an equine immunomodulatory agent; if the subject is a donkey, the immunomodulatory agent is a donkey immunomodulatory agent; if the subject is an elephant, the immunomodulatory agent is an elephant immunomodulatory agent; if the subject is a sheep, the immunomodulatory agent is a sheep immunomodulatory agent; if the subject is a goat, the immunomodulatory agent is a goat immunomodulatory agent; if the subject is a pig, the immunomodulatory agent is a pig immunomodulatory agent; if the subject is a rabbit, the immunomodulatory agent is a rabbit immunomodulatory agent. if the subject is a mouse, the immunomodulatory substance is a mouse immunomodulatory substance; if the subject is a rat, the immunomodulatory substance is a rat immunomodulatory substance; if the subject is a camel, the immunomodulatory substance is a camel immunomodulatory substance; if the subject is a dromedary, the immunomodulatory substance is a dromedary immunomodulatory substance; if the subject is a llama, the immunomodulatory substance is a llama immunomodulatory substance; if the subject is an alpaca, the immunomodulatory substance is an alpaca immunomodulatory substance; if the subject is a dog, the immunomodulatory substance is a canine immunomodulatory substance; and / or if the subject is a cat, the immunomodulatory substance is a feline immunomodulatory substance.

[0139] Preferably, the immunomodulatory substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits, is not an endogenous immunomodulatory substance of the subject. In other words, preferably, the immunomodulatory substance is not an immunomodulatory substance isolated from the subject's body, i.e., from the individual subject being treated or prevented.

[0140] Preferably, the immunomodulatory substance referred to in any of the embodiments described herein, particularly the immunomodulatory substance for use in accordance with the invention and / or steps (B), (B1), and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices, and / or kits, can be, and preferably is, a recombinant immunomodulatory substance produced by any recombinant expression technology known to those of skill in the art, a chemically synthesized immunomodulatory substance synthesized by any production technology known to those of skill in the art, an artificially produced immunomodulatory substance produced by any production technology known to those of skill in the art, a naturally occurring immunomodulatory substance obtained from a natural source such as an animal or human, or any combination thereof. More preferably, the immunomodulatory substance is a recombinant immunomodulatory substance, a chemically synthesized immunomodulatory substance, an artificially produced immunomodulatory substance, or any combination thereof, and even more preferably, a recombinant immunomodulatory substance.

[0141] Furthermore, the immunomodulatory substances for use in accordance with the invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits may be derivatized, stabilized, fused to other proteins or peptides, conjugated with polymers, contain amino acid analogs or artificial amino acids, covalently or non-covalently modified, e.g., by post-translational modification, e.g., glycosylated or methylated, and / or oligomerized, e.g., dimerized or trimerized, protein analogs, protein variants, or otherwise, so long as they are capable of and / or do act on PBMCs. More preferably, the modification pattern and / or oligomerization state is similar or identical to a peptide, protein, or fragment of any of these, that naturally occurs in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, and even more preferably a subject as defined in any of the embodiments in accordance with the invention.

[0142] The advantage of such similarity or identity to immunomodulatory substances naturally occurring in the subject's body is that, particularly in the case of identity, the generation of an immune response against such substances and their elimination by the subject's immune system cannot be predicted (e.g., antibody production). This is particularly likely to be the case when the immunomodulatory substance is vital to the subject. This is the case, for example, when the immunomodulatory substance is a cytokine, particularly IFN-γ (interferon gamma), IL-2 (interleukin 2), IL-4 (interleukin 4), or BDNF (brain-derived neurotrophic factor). Immune system attack against such immunomodulatory substances would most likely be life-threatening or even fatal, and therefore would be unexpected. The situation is different for biologics and biosimilars, such as TNF-α inhibitor (tumor necrosis factor alpha inhibitor) or IL-6 inhibitor (interleukin-6 inhibitor) monoclonal antibodies. These are artificial substances that do not naturally occur in the subject's body. Sooner or later, they will usually be recognized as foreign and neutralized by the subject's immune system. This is conceivable because their removal by the subject's immune system does not have life-threatening consequences for immune system homeostasis. Indeed, as soon as suitable antibodies are formed, such antibodies will remove or neutralize, for example, a biologic or biosimilar. As a result, its effectiveness is lost, at least to some extent, and clinical resistance to treatment with the biologic or biosimilar is observed in the subject. As a result, the biologic or biosimilar becomes ineffective. Furthermore, this lack of effectiveness is typically permanent and continues throughout the subject's life. Memory B cells usually remain as remnants of the immune response in the body for the remainder of the subject's life. Thereby, they repeatedly ensure the removal of the biologic or biosimilar for the remainder of the subject's life. Furthermore, this is not reversible and is difficult to replace. Therefore, once such antibodies are generated, in this event, the biologic or biosimilar cannot be effectively applied again in this particular individual.Contrary to, for example, biologics or biosimilars, such loss of effectiveness is not expected with respect to the immunomodulatory substances preferably used in the present invention for the reasons explained above.

[0143] An additional advantage of such similarity or identity to the immunomodulatory substance naturally occurring in the subject's body is that, especially in the case of identity, adverse side effects such as fatigue and drug intolerance are less likely to be observed or not observed, and should not be expected.However, this is often the case, for example, with biologics and biosimilars.Patients treated according to the present invention feel more energetic and even more energetic, possibly because the debilitating inflammation of the subject's body is suppressed (for example, as indicated by a decrease in CRP (C-reactive protein) amount, a decrease in BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) value, or a decrease in HAQ (Health Assessment Questionnaire) value).The therapy of the present invention does not add any adverse side effects or incompatibility, even in long-term use for more than one year.

[0144] Furthermore, glucocorticoids are frequently used in the treatment of inflammatory diseases. Because glucocorticoids are highly similar to or even identical to substances naturally occurring in the body of a subject, it should be mentioned that: In conventional therapy, glucocorticoids must be administered at high concentrations to be effective. Due to this fact, with long-term use, they produce severe adverse effects, even stronger in adults and children. It is a general concern in medicine to administer drugs and preparations at the lowest concentration that is still effective. However, for example, lowering the dosage of glucocorticoids is not possible to confer their beneficial effects. Therefore, conventional therapy must make an unpleasant comparison between side effects and therapeutic effects.

[0145] Similarly, immunomodulatory substances, particularly IFN-γ and IL-2, are also used in conventional therapy or therapeutic trials, often at very high doses. Furthermore, it has previously been reported that administration of high concentrations of, for example, IFN-γ (50,000 ng recombinant IFN-γ) was not even more effective than placebo in patients with rheumatoid arthritis ("A randomized, double-blind study comparing 24-week treatment with recombinant interferon-γ versus placebo in the treatment of rheumatoid arthritis," Eric M. Veys MD, PhD, Charles-Joel Menkes MD, PhD, Paul Emery FRCP, First published: January 1997, https: / / doi.org / 10.1002 / art.1780400110).

[0146] In the present invention, for example, the highest preferred concentration of IFN-γ is 1,500 ng, 33-fold lower than the concentration used by Eric et al. In examples of the present invention, even an amount of 5 ng of IFN-γ is effectively used, which is a much greater 10,000-fold lower than the amount used by Eric et al.

[0147] Therefore, the present invention is based on the further surprising finding that immunomodulatory substances can be administered at extremely low concentrations while still being effective.

[0148] Such low concentrations typically do not result in a systemic increase of the immunomodulatory substance in the subject's body, or at least not in a systemic increase that is likely to be effective (systemic effective increase). The systemic homeostasis of the immune system is unlikely to be altered. The locally administered low amount can be easily handled by the subject's metabolism. In view of these, adverse side effects should not be expected even in long-term use, and a comparison between side effects and therapeutic effects is not necessary.

[0149] Furthermore, administering lower doses of immunomodulatory substances even improves the efficacy of treatment, the reliability of therapeutic success, and the replicability in larger patient populations.

[0150] Without wishing to be bound by theory, it is believed that by administering an extremely low amount of an immunomodulatory substance, the terminal phase of an inflammatory response may be similar, for example, locally in the skin. This avoids the generation of highly aggressive pro-inflammatory cytotoxic T cells, while promoting the generation of immunosuppressive T cells, such as helper T cells, or a subset thereof, and particularly regulatory T cells. This promotes the desired and therapeutic anti-inflammatory effect while preventing undesirable and harmful pro-inflammatory effects. It is noted that cytotoxic T cells are, in a sense, pro-inflammatory counteractors of anti-inflammatory helper T cells, or a subset thereof, and particularly regulatory T cells. However, when administering a high amount of an immunomodulatory substance, the desired anti-inflammatory effect may be counteracted or even exceeded by the undesirable pro-inflammatory effect. This may be a possible explanation for why the high concentration administered in Eric et al. did not show any significant beneficial effect over placebo.

[0151] Specifically, a healthy immune system generates a large number of cytotoxic T cells during an inflammatory response to neutralize harmful antigens. As mentioned above, these cells are highly aggressive. The presence of antigens in combination with immunomodulatory substances such as IFN-γ causes naive T cells to develop into cytotoxic T cells. Ultimately, at the end of the inflammatory response, all antigens are neutralized, leaving excess cytotoxic T cells, which are relieved of their duties. To prevent these highly aggressive cells from causing damage elsewhere in the body, the immune system provides, for example, regulatory T cells. As previously mentioned, such regulatory T cells can function as immunosuppressive counterparts of cytotoxic T cells. They ensure that the degree of immune activation is limited. At the end of the inflammatory response, all antigens are neutralized, but immunomodulatory substances such as IFN-γ are still present. As a result, at the end of the inflammatory response, the environment has shifted to favor regulatory T cells and / or helper T cells, or subsets thereof. Without the presence of antigen in the simultaneous presence of an immunomodulatory substance such as IFN-γ, the trailing or subsequent naive T cells will no longer develop into cytotoxic T cells; they will mature or develop into regulatory T cells.

[0152] Without wishing to be bound by theory, the present invention is believed to form immunosuppressive T cells, such as regulatory and / or helper T cells, in skin that is free or essentially free of antigens / autoantigens / allergens.For example, it is further believed that immunosuppressive T cells, such as regulatory T cells and helper T cells, or a subset thereof, are generated by accumulating PBMCs in the skin and contacting them with an immunomodulatory substance while simultaneously avoiding contact with antigens, autoantigens, or allergens.However, when a high amount of immunomodulatory substance is administered, it is believed that the concentration of the immunomodulatory substance will increase systemically to an effective extent, i.e., a systemic effective increase will occur.Therefore, while a large amount of autoantigens, i.e., joint tissue, is simultaneously present, for example, rheumatoid inflamed joints will also be stimulated by an effective amount of immunomodulatory substance such as IFN-γ.As a result, cytotoxic T cells may be generated in the joint.Auto-attack in the joint may even increase. The beneficial suppressive effects of, for example, regulatory T cells generated within the skin may be prevented, counteracted or even exceeded.

[0153] In short, without wishing to be bound by theory, it is believed that naive PBMCs, particularly naive T cells, are the target of the present invention. By using, for example, skin as an in vivo incubator for naive T cells, helper T cells, or a subset thereof, and regulatory T cells can be specifically and locally generated. Therefore, the latter are considered to be effectors that migrate in large numbers and exert their beneficial anti-inflammatory effects where needed. At the same time, the generation of pro-inflammatory cytotoxic T cells is preferably avoided elsewhere in the subject's body.

[0154] Therefore, in any of the embodiments described herein, it is preferable to administer the immunomodulatory substance at a sufficiently low dose to avoid a systemic increase, particularly an effective systemic increase, of the immunomodulatory substance in the subject's body. This will avoid the generation of increased concentrations of the immunomodulatory substance at sites of inflammation, such as inflamed joints. As already mentioned above, for example, naive T cells can mature into cytotoxic T cells in the presence of antigens / autoantigens / allergens. These T cells function in a pro-inflammatory manner, thereby reducing, canceling, or even reversing the beneficial anti-inflammatory effects conferred by regulatory T cells and / or helper T cells, or subsets thereof. Therefore, administering the immunomodulatory substance at a sufficiently low dose is believed to exclusively promote the generation of regulatory T cells and / or helper T cells, or subsets thereof, locally in the skin, while preventing the generation of cytotoxic T cells elsewhere in the subject's body.

[0155] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1), and / or (C), the immunomodulatory agent is administered in an amount that does not cause a systemic increase, more preferably an effective systemic increase, in the concentration of the immunomodulatory agent in the subject, preferably the subject's blood, and / or that causes a systemic increase in the concentration of the immunomodulatory agent. Preferably, the immunomodulatory agent is administered in an amount that is sufficiently low that the systemic increase is ineffective.

[0156] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1), and / or (C), the immunomodulatory agent is administered in an amount that causes a local increase, preferably an effective local increase, in the concentration of the immunomodulatory agent in the subject, preferably in the skin tissue of the subject, where skin tissue is preferred because, unlike administration into the blood, there is no or less washout and dilution of the immunomodulatory agent.

[0157] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the production of an increased concentration, preferably an effective increased concentration, of the administered immunomodulatory agent is only local and not systemic in the subject.

[0158] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the immunomodulatory agent is administered in an amount that does not cause systemic activation, preferably effective systemic activation, of the immunomodulatory agent's individual receptors and / or does not cause systemic production, preferably effective systemic production, of the immunomodulatory agent, preferably in the subject.

[0159] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the immunomodulatory agent is administered in an amount that causes local activation, preferably effective local activation, of the immunomodulatory agent's respective receptor and / or causes local production, preferably effective local production, of the immunomodulatory agent, preferably within the subject. Preferably, the activation and / or production, more preferably effective production and / or effective activation, is only local and not systemic in the subject.

[0160] Preferably, the immunomodulatory substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or the immunomodulatory substance of steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits, is a cytokine-like functional substance, preferably a cytokine or any derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof.

[0161] In the present invention, the expressions "cytokine-like functional substance," "interferon-like functional substance," "interleukin-like functional substance," "neutrophin-like functional substance," or any similar expressions refer to a substance that exerts, directly or indirectly, e.g., after being metabolized, an effect similar to or identical to the effect exerted by the substance itself in the body of a subject, and in each case also encompasses the substance itself, i.e., a "cytokine-like functional substance" encompasses cytokines, an "interferon-like functional substance" encompasses interferons, an "interleukin-like functional substance" encompasses interleukins, and a "neutrophin-like functional substance" encompasses neurotrophic factors, etc.

[0162] This also applies when used in the following terms herein, for example, "cytokine and / or cytokine-like functional substance" or "cytokine or cytokine-like functional substance" or similar terms, i.e., in these terms, the expression "cytokine-like functional substance" refers to the cytokine itself and any substance that exerts, directly or indirectly, for example after being metabolized, an effect similar to or identical to the effect exerted by the cytokine itself in the body of a subject.

[0163] The expression "cytokine-like functional substance" or "cytokine-like functional substances", when referred to in any of the embodiments described herein, may be, and preferably is, any substance that exerts an effect similar to or identical to that of a cytokine in the body of a subject when administered thereto. A cytokine-like functional substance can include precursors, prodrugs and propeptides of such substances that are not normally active as such, i.e., do not have immunomodulatory activity, but which are converted into an actual active cytokine-like functional substance when used in accordance with the present invention. Preferably, therefore, it is any substance, molecule, peptide, protein, protein analogue, protein variant, derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or any derivative, fragment and / or pharmaceutically acceptable salt of any of these. Thus, a cytokine-like functional substance is: - activates or is capable of activating individual cytokine receptors of cells, which may be, for example, receptors of PBMCs; and / or - causing or causing or capable of causing or causing the production of cytokines and / or cytokine-like functional substances It is possible.

[0164] More preferably, the cytokine-like functional substance activates or is capable of activating an individual cytokine receptor. The activation or ability to activate an individual cytokine receptor may be direct and / or indirect.

[0165] Preferably, the cytokine-like functional substance activates or is capable of activating individual cytokine receptors in the skin of a subject. The cytokine-like functional substance can be any naturally occurring or artificial cytokine-like functional substance, as long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and is particularly capable of activating individual cytokine receptors. Preferably, the cytokine-like functional substance is known to those skilled in the art as of the filing date of the present application.

[0166] More preferably, the cytokine-like functional substance is any peptide, protein, protein analog, protein variant or any derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt of any of these.

[0167] In a preferred embodiment, the cytokine-like functional substance may be, inter alia, a cytokine and / or its derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts thereof, as detailed below.

[0168] More preferably, the cytokine-like functional substance is a cytokine and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof.

[0169] The expression "cytokine" or "cytokines" when referred to in any of the embodiments described herein should preferably be interpreted broadly. Typically, a cytokine activates or is capable of activating a respective cytokine receptor on a cell. The cytokine receptor may be, for example, a receptor on PBMC. Preferably, the activation or ability to activate is within the skin of a subject, more preferably in a locally effective amount within the skin of a subject, and even more preferably not in a systemically effective amount within the body of a subject. Preferably, the cytokine may be any type of cytokine known to those skilled in the art. Furthermore, the present invention encompasses the use or medical use of precursors, prodrugs, and propeptides of such cytokines that are not normally active as such, i.e., do not have immunomodulatory activity, but are converted into an actual active cytokine upon use in accordance with the present invention. Thus, they can be used in the methods or medical uses as described herein, or in the preparation of pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices, and / or kits as described herein.

[0170] Preferably, the cytokine may be any peptide, protein, protein analogue, protein variant and / or any derivative or pharmaceutically acceptable salt of any of these.

[0171] The cytokine does not necessarily have to be derived from or identical to a cytokine of the same genus and / or species to which the subject belongs, but can be any naturally occurring or artificial cytokine, as long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and in particular is capable of activating individual cytokine receptors. Preferably, the biological activity of the cytokine and / or cytokine-like functional substance is sufficient to achieve treatment and / or prevention of an inflammatory disease, immunological disease and / or autoimmune disease, preferably in the subject.

[0172] Cytokines and / or cytokine-like functional substances typically act on cells by binding to and activating respective cytokine receptors on the cells. Activation of the respective receptors therefore typically results in the cellular effects as described above for immunomodulatory substances. Therefore, any embodiments referred to herein for immunomodulatory substances in relation to their effects on cells such as PBMCs are independently applicable mutatis mutandis to cytokines and cytokine-like functional substances.

[0173] The activation or ability to activate individual cytokine receptors by cytokines and / or cytokine-like functional substances can be direct and / or indirect.

[0174] The expression "directly", when referred to in any of the embodiments described herein, typically in the context of "activating" and / or "capable of activating" a respective receptor, means that the cytokine or cytokine-like functional substance itself functions or is capable of functioning as an activator of the respective receptor of the cytokine or cytokine-like functional substance on a cell, etc.

[0175] The expression "indirectly", when referred to in any of the embodiments described herein, typically means that the cytokine or cytokine-like functional substance is any substance that causes or induces, or is capable of causing or inducing, the production of a cytokine or cytokine-like functional substance, in particular a precursor, propeptide, or prodrug. In other words, a cytokine or cytokine-like functional substance can encompass substances that are not normally active in themselves, i.e., do not have immunomodulatory activity such as receptor activation or activation ability, but that are converted into an actual cytokine or cytokine-like functional substance when used in accordance with the present invention. Thereby, the desired activation of an individual cytokine receptor is achieved indirectly. This can be, for example, when the cytokine or cytokine-like functional substance is any substance such as: - an inducer that induces cells to produce and / or secrete cytokines or cytokine-like functional substances, and such cells may be any cells capable of producing and / or secreting cytokines or cytokine-like functional substances, such as PBMCs or any subpopulation of PBMCs or any cells other than PBMCs, preferably dendritic cells, more preferably skin-resident dendritic cells such as Langerhans cells; - for example, precursors of cytokines or cytokine-like functional substances that are metabolized by the body of a subject to produce cytokines or cytokine-like functional substances. Precursors of immunomodulatory substances include, for example, peptides, proteins, protein analogs, protein variants, propeptides, derivatives thereof, RNA, DNA, salts, capped immunomodulatory substances, etc., among others; - inhibitors of substances, enzymes or factors that prevent the expression, interaction, production, secretion and / or activity of cytokines or cytokine-like functional substances, such as particles or nanoparticles or cap structures. Cytokines or cytokine-like functional substances can, for example, be loaded into particles for delivery. These particles can sterically prevent and protect the substance from interacting with its target, e.g., receptor, and the substance can only exert its effect after release from the particle, e.g., in the patient's body; - prodrugs of cytokines or cytokine-like functional substances; - muteins of cytokines or cytokine-like functional substances; - Biopharmaceuticals, such as immunomodulatory biologics, biosimilars, biomimetics, biobetters and / or biosuperiors; and / or - Codrugs of cytokines or cytokine-like functional substances.

[0176] Preferably, the cytokine and / or cytokine-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is capable of and / or acts on PBMCs by attracting, proliferating, differentiating and / or maturing, even more preferably by proliferating, differentiating and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the cytokine and / or cytokine-like functional substance is capable of and / or causes PBMCs to attract, proliferate, differentiate and / or mature. Even more preferably, the cytokine and / or cytokine-like functional substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the cytokine and / or cytokine-like functional substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the cytokine and / or cytokine-like functional substance is capable of and / or causes PBMCs to differentiate and / or mature. Preferably, the PBMCs are naive PBMCs, more preferably lymphocytes, even more preferably T cells and / or B cells, also more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, even more preferably naive T cells.

[0177] More preferably, the cytokine and / or cytokine-like functional substance is capable of and / or does act directly and / or indirectly on PBMCs.

[0178] More preferably, the cytokine and / or cytokine-like functional substance is capable of and / or acts directly and / or indirectly on PBMCs in the subject, more preferably in the skin of the subject, as defined in any of the embodiments according to the present invention.

[0179] Even more preferably, the cytokine and / or cytokine-like functional substance is capable of and / or directly causes the proliferation, differentiation and / or maturation of naive T cells in a subject as defined in any of the embodiments according to the present invention, more preferably in the skin of the subject.

[0180] Unless otherwise stated, the descriptions and definitions of immunomodulatory substances set forth above are applicable mutatis mutandis to cytokines and / or cytokine-like functional substances independently. Particularly, unless otherwise stated, the descriptions and definitions of immunomodulatory substances with respect to acting or being capable of acting "directly" and "indirectly" on PBMCs are applicable mutatis mutandis to cytokines and / or cytokine-like functional substances independently.

[0181] Preferably, the cytokine and / or cytokine-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is similar or identical, preferably identical, to any cytokine and / or cytokine-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body, more preferably a subject as defined in any of the embodiments according to the present invention. More preferably, the cytokine and / or cytokine-like functional substance is similar or identical, preferably identical, to any peptide, protein or fragment of any of these of a cytokine and / or cytokine-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0182] More preferably, the cytokine and / or cytokine-like functional substance has 70% or more, even more preferably 85% or more, still more preferably 90% or more, still more preferably 95% or more, even more preferably 97% or more, still more preferably 98% or more, and still more preferably 99% or more and up to 100% amino acid sequence identity to any peptide, protein, or fragment of any of these, of a cytokine and / or cytokine-like functional substance that is naturally occurring in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably in a subject as defined in any of the embodiments according to the present invention. Preferably, the amino acid sequence identity includes amino acid residue substitutions, insertions, and / or deletions relative to the naturally occurring peptide, protein, or fragment of any of these. Preferably, the total number of substitutions, insertions, and / or deletions of amino acid residues, or the total number of substitutions, insertions, and / or deletions combined, is 60 or less, more preferably 40 or less, even more preferably 20 or less, still more preferably 12 or less, still more preferably 8 or less, even more preferably 4 or less, still more preferably 2 or less and zero or more, and even more preferably zero.

[0183] Even more preferably, the cytokine and / or cytokine-like functional substance is identical to, or refers to amino acid sequence identity with, an endogenous immunomodulatory substance of the same genus and / or species to which the subject belongs. The expression "identical" typically means in this particular context that the cytokine and / or cytokine-like functional substance is identical to, a cytokine and / or cytokine-like functional substance of the same genus and / or species to which the subject belongs, with respect to its primary, secondary, tertiary and quaternary protein structure, and more preferably also taking into account modification patterns, in particular glycosylation.

[0184] Preferably, the cytokine and / or cytokine-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is derived from an individual belonging to the same genus and / or species as the subject, or is identical to the cytokine and / or cytokine-like functional substance of the same genus and / or species to which the subject belongs. For example, if the subject is a human, the cytokine and / or cytokine-like functional substance is a human cytokine and / or cytokine-like functional substance; if the subject is a cow, the cytokine and / or cytokine-like functional substance is a bovine cytokine and / or cytokine-like functional substance; if the subject is a horse, the cytokine and / or cytokine-like functional substance is an equine cytokine and / or cytokine-like functional substance; if the subject is a donkey, the cytokine and / or cytokine-like functional substance is a donkey cytokine and / or cytokine-like functional substance; if the subject is an elephant, the cytokine and / or cytokine-like functional substance is an elephant cytokine and / or cytokine-like functional substance; if the subject is a sheep, the cytokine and / or cytokine-like functional substance is a human cytokine and / or cytokine-like functional substance; if the subject is a cow, the cytokine and / or cytokine-like functional substance is a bovine cytokine and / or cytokine-like functional substance; if the subject is a horse, the cytokine and / or cytokine-like functional substance is an equine cytokine and / or cytokine-like functional substance; if the subject is a donkey, the cytokine and / or cytokine-like functional substance is a donkey cytokine and / or cytokine-like functional substance; if the subject is an elephant, the cytokine and / or cytokine-like functional substance is an elephant cytokine and / or cytokine-like functional substance; the substance is a sheep cytokine and / or cytokine-like functional substance; if it is a goat, the cytokine and / or cytokine-like functional substance is a goat cytokine and / or cytokine-like functional substance; if it is a pig, the cytokine and / or cytokine-like functional substance is a pig cytokine and / or cytokine-like functional substance; if it is a rabbit, the cytokine and / or cytokine-like functional substance is a rabbit cytokine and / or cytokine-like functional substance; if it is a mouse, the cytokine and / or cytokine-like functional substance is a mouse cytokine and / or cytokine-like functional substance; if it is a rat, the cytokine and / or cytokine-like functional substance is a rat cytokine and / or cytokine-like functional substance;When the animal is a camel, the cytokine and / or cytokine-like functional substance is a camel cytokine and / or cytokine-like functional substance; when the animal is a dromedary, the cytokine and / or cytokine-like functional substance is a dromedary cytokine and / or cytokine-like functional substance; when the animal is a llama, the cytokine and / or cytokine-like functional substance is a llama cytokine and / or cytokine-like functional substance; when the animal is an alpaca, the cytokine and / or cytokine-like functional substance is an alpaca cytokine and / or cytokine-like functional substance; when the animal is a dog, the cytokine and / or cytokine-like functional substance is a dog cytokine and / or cytokine-like functional substance; and / or when the animal is a cat, the cytokine and / or cytokine-like functional substance is a feline cytokine and / or cytokine-like functional substance;

[0185] Preferably, the cytokine and / or cytokine-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is not an endogenous cytokine and / or cytokine-like functional substance of the subject. In other words, preferably, the cytokine and / or cytokine-like functional substance is not a cytokine and / or cytokine-like functional substance isolated from the subject's body, i.e., from the individual subject to be treated or prevented.

[0186] Preferably, the cytokine and / or cytokine-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may be, and preferably is, a recombinant cytokine and / or cytokine-like functional substance produced by any recombinant expression technology known to those skilled in the art, a chemically synthesized cytokine and / or cytokine-like functional substance synthesized by any production technology known to those skilled in the art, an artificially produced cytokine and / or cytokine-like functional substance produced by any production technology known to those skilled in the art, a naturally occurring cytokine and / or cytokine-like functional substance obtained from a natural source such as an animal or human, or any combination thereof. More preferably, the cytokine and / or cytokine-like functional substance is a recombinant cytokine and / or cytokine-like functional substance, a chemically synthesized cytokine and / or cytokine-like functional substance, an artificially produced cytokine and / or cytokine-like functional substance or any combination thereof, and even more preferably a recombinant cytokine and / or cytokine-like functional substance.

[0187] Furthermore, the cytokines and / or cytokine-like functional substances for use according to the present invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits may be derivatized, stabilized, fused to other proteins or peptides, conjugated with polymers, contain amino acid analogs or artificial amino acids, covalently or non-covalently modified, e.g., by post-translational modification, e.g., glycosylated or methylated, and / or oligomerized, e.g., dimerized or trimerized, or not, so long as they are capable of and / or act on PBMCs. More preferably, the modification pattern and / or oligomerization state is similar or identical to a peptide, protein or a fragment of any of these that occurs naturally in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0188] Preferably, in any of the embodiments described herein, the cytokine and / or cytokine-like functional substance is administered in a sufficiently low amount to avoid a systemic increase in the concentration of the cytokine and / or cytokine-like functional substance in the subject's body. This is intended to avoid the generation of increased concentrations of cytokines and / or cytokine-like functional substances at inflammation sites, such as inflamed joints. As already mentioned above, for example, naive T cells can mature into cytotoxic cells that can function as pro-inflammatory cells in the presence of antigens / autoantigens / allergens. This reduces, cancels, or even reverses the beneficial effects achieved by the present invention, particularly the anti-inflammatory effects of the regulatory T cells and / or helper T cells, or subsets thereof, that may be generated.

[0189] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the cytokine and / or cytokine-like functional substance is administered in an amount that does not cause a systemic increase, more preferably an effective systemic increase, in the concentration of the cytokine and / or cytokine-like functional substance in the subject, preferably the blood of the subject, and / or that causes a systemic increase in the concentration of the cytokine and / or cytokine-like functional substance. Preferably, the cytokine and / or cytokine-like functional substance is administered in an amount that is sufficiently low so that the systemic increase is ineffective.

[0190] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the cytokine and / or cytokine-like functional substance is administered in an amount that causes a local increase, preferably an effective local increase, in the concentration of the cytokine and / or cytokine-like functional substance in the subject, preferably in the skin tissue of the subject. Skin tissue is preferred because, unlike administration into the blood, there is no or less washout and dilution of the cytokine and / or cytokine-like functional substance.

[0191] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the production of an increased concentration, preferably an effective increased concentration, of the administered cytokine and / or cytokine-like functional substance is only local and not systemic in the subject.

[0192] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the cytokine and / or cytokine-like functional substance is administered in an amount that does not cause systemic activation, preferably effective systemic activation, of the cytokine and / or cytokine-like functional substance's respective receptors, and / or does not cause systemic production, preferably effective systemic production, of the cytokine and / or cytokine-like functional substance, preferably in the subject.

[0193] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the cytokine and / or cytokine-like functional substance is administered in an amount that causes local activation, preferably effective local activation, of the cytokine and / or cytokine-like functional substance's respective receptor, preferably in the subject, and / or causes local production, preferably effective local production, of the cytokine and / or cytokine-like functional substance. Preferably, the activation and / or production, more preferably effective production and / or effective activation, is only local and not systemic in the subject.

[0194] Preferably, the cytokine-like functional substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or the immunomodulatory substance of steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is a cytokine-like functional substance, more preferably an interferon-like functional substance, an interleukin-like functional substance and / or a neurotrophic factor-like functional substance.

[0195] Preferably, the cytokine as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is a cytokine, more preferably an interferon, interleukin, neurotrophic factor, colony-stimulating factor, tumor necrosis factor and / or chemokine, even more preferably an interferon, interleukin and / or neurotrophic factor, also more preferably an interferon and / or interleukin.

[0196] The expression "interferon-like functional substance" or "interferon-like functional substances" when referred to in any of the embodiments described herein may refer to any substance that exerts an effect similar to or identical to that of interferon in the body of a subject when administered thereto, and preferably refers to such a substance. Interferon-like functional substances can include precursors, prodrugs, and propeptides of such substances that are not normally active as they are, i.e., do not have immunomodulatory activity, but are converted into active interferon-like functional substances when used according to the present invention. Therefore, preferably, it is any substance, molecule, peptide, protein, protein analog, protein variant, derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, and / or any derivative, fragment, and / or pharmaceutically acceptable salt of any of these. Thus, an interferon-like functional substance is: - activates or is capable of activating individual interferon receptors of cells, which may be, for example, receptors of PBMCs; and / or - causing or inducing or capable of causing or inducing the production of interferon and / or interferon-like functional substances It is possible.

[0197] More preferably, the interferon-like functional substance activates or is capable of activating an individual interferon receptor. The activation or ability to activate an individual interferon receptor can be direct and / or indirect.

[0198] Preferably, the interferon-like functional substance activates or is capable of activating individual interferon receptors in the skin of a subject.The interferon-like functional substance can be any naturally occurring or artificial interferon-like functional substance, as long as it has sufficient biological activity, i.e., effective cross-reactivity in a subject, and is particularly capable of activating individual interferon receptors.Preferably, the interferon-like functional substance is known to those skilled in the art as of the filing date of the present invention.

[0199] More preferably, the interferon-like functional substance is any peptide, protein, protein analog, protein variant or any derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt of any of these.

[0200] In a preferred embodiment, the interferon-like functional substance may be, inter alia, an interferon and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof, as detailed below.

[0201] More preferably, the interferon-like functional substance is an interferon and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof.

[0202] The expression "interferon" or "interferons" when referred to in any of the embodiments described herein should preferably be interpreted broadly. Typically, interferons activate or are capable of activating individual interferon receptors on cells. The interferon receptors may be, for example, receptors on PBMCs. Preferably, the activation or ability to activate is within the skin of a subject, more preferably in a locally effective amount within the skin of a subject, and even more preferably not in a systemically effective amount within the body of a subject. Preferably, the interferon may be any type of interferon known to those skilled in the art. Furthermore, the present invention encompasses the use or medical use of precursors, prodrugs, and propeptides of such interferons that are not normally active as such, i.e., do not have immunomodulatory activity, but are converted into active interferons upon use in accordance with the present invention. Thus, they can be used in the methods or medical uses described herein, or in the preparation of pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices, and / or kits described herein.

[0203] Preferably, the interferon may be any peptide, protein, protein analogue, protein variant and / or any derivative or pharmaceutically acceptable salt of any of these.

[0204] The interferon does not necessarily have to be derived from or be identical to the interferon of the same genus and / or species to which the subject belongs, but can be any naturally occurring or artificial interferon, as long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and in particular is capable of activating individual interferon receptors. Preferably, the biological activity of the interferon and / or interferon-like functional substance is sufficient to achieve treatment and / or prevention of inflammatory diseases, immunological diseases and / or autoimmune diseases in the subject.

[0205] Interferons and / or interferon-like functional substances typically act on cells by binding to and activating individual interferon receptors on the cells. Activation of the individual receptors therefore typically results in the cellular effects as described above for immunomodulatory substances. Therefore, any embodiment referred to herein for immunomodulatory substances in relation to their effects on cells such as PBMCs is independently applicable mutatis mutandis to interferons and interferon-like functional substances.

[0206] The activation or ability to activate individual interferon receptors by interferons and / or interferon-like functional substances can be direct and / or indirect.

[0207] Unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances set forth above are applicable mutatis mutandis to interferons and / or interferon-like functional substances independently. In particular, unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances that "directly" and "indirectly" activate or are capable of activating individual interferon receptors are applicable mutatis mutandis to interferons and / or interferon-like functional substances independently.

[0208] Preferably, the interferon and / or interferon-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is capable of and / or acts on PBMCs by attracting, proliferating, differentiating and / or maturing, even more preferably by proliferating, differentiating and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the interferon and / or interferon-like functional substance is capable of and / or causes PBMCs to attract, proliferate, differentiate and / or mature. Even more preferably, the interferon and / or interferon-like functional substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the interferon and / or interferon-like functional substance is capable of differentiating and / or maturing PBMCs and / or causes the differentiation and / or maturation of PBMCs. Preferably, the PBMCs are naive PBMCs, more preferably lymphocytes, even more preferably T cells and / or B cells, also more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0209] More preferably, the interferon and / or interferon-like functional substance is capable of and / or does act directly and / or indirectly on PBMCs.

[0210] More preferably, the interferon and / or interferon-like functional substance is capable of and / or acts directly and / or indirectly on PBMCs in the subject, more preferably in the skin of the subject, as defined in any of the embodiments according to the present invention.

[0211] Even more preferably, the interferon and / or interferon-like functional substance is capable of and / or directly causes the proliferation, differentiation and / or maturation of naive T cells in the subject, more preferably in the skin of the subject, as defined in any of the embodiments according to the present invention.

[0212] Unless otherwise stated, the descriptions and definitions of immunomodulatory substances set forth above are applicable mutatis mutandis to interferon and / or interferon-like functional substances, independently. In particular, unless otherwise stated, the descriptions and definitions of immunomodulatory substances that act or are capable of acting "directly" and "indirectly" on PBMCs are applicable mutatis mutandis to interferon and / or interferon-like functional substances, independently.

[0213] Preferably, the interferon and / or interferon-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is similar or identical, preferably identical, to any interferon and / or interferon-like functional substance naturally occurring in a vertebrate, preferably human or mammalian body, more preferably in a subject as defined in any of the embodiments according to the present invention. More preferably, the interferon and / or interferon-like functional substance is similar or identical, preferably identical, to any peptide, protein or fragment of any of these of an interferon and / or interferon-like functional substance naturally occurring in a vertebrate, preferably human or mammalian body as defined above, more preferably in a subject as defined in any of the embodiments according to the present invention.

[0214] More preferably, the interferon and / or interferon-like functional substance has 70% or more, even more preferably 85% or more, still more preferably 90% or more, still more preferably 95% or more, even more preferably 97% or more, even more preferably 98% or more, and still more preferably 99% or more and 100% or less amino acid sequence identity to any peptide, protein, or fragment of any of these of an interferon and / or interferon-like functional substance naturally occurring in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably in a subject as defined in any of the embodiments according to the present invention. Preferably, the amino acid sequence identity includes substitutions, insertions, and / or deletions of amino acid residues relative to the naturally occurring peptide, protein, or fragment of any of these. Preferably, the total number of substitutions, insertions, and / or deletions of amino acid residues, or the total number of substitutions, insertions, and / or deletions combined, is 60 or less, more preferably 40 or less, even more preferably 20 or less, still more preferably 12 or less, still more preferably 8 or less, even more preferably 4 or less, still more preferably 2 or less and zero or more, and even more preferably zero.

[0215] Even more preferably, the interferon and / or interferon-like functional substance is identical to, or refers to amino acid sequence identity with, an endogenous immunomodulatory substance of the same genus and / or species to which the subject belongs. The expression "identical" typically means in this particular context that the interferon and / or interferon-like functional substance is identical to, an interferon and / or interferon-like functional substance of the same genus and / or species to which the subject belongs, with respect to its primary, secondary, tertiary and quaternary protein structure, and more preferably also taking into account modification patterns, in particular glycosylation.

[0216] Preferably, the interferon and / or interferon-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is derived from an individual belonging to the same genus and / or species as the subject, or is identical to the interferon and / or interferon-like functional substance of the same genus and / or species to which the subject belongs. For example, if the subject is a human, the interferon and / or interferon-like functional substance is a human interferon and / or interferon-like functional substance; if the subject is a cow, the interferon and / or interferon-like functional substance is a bovine interferon and / or interferon-like functional substance; if the subject is a horse, the interferon and / or interferon-like functional substance is an equine interferon and / or interferon-like functional substance; if the subject is a donkey, the interferon and / or interferon-like functional substance is a donkey interferon and / or interferon-like functional substance; if the subject is an elephant, the interferon and / or interferon-like functional substance is an elephant interferon and / or interferon-like functional substance. when it is a sheep, the interferon and / or interferon-like functional substance is a sheep interferon and / or interferon-like functional substance; when it is a goat, the interferon and / or interferon-like functional substance is a goat interferon and / or interferon-like functional substance; when it is a pig, the interferon and / or interferon-like functional substance is a pig interferon and / or interferon-like functional substance; when it is a rabbit, the interferon and / or interferon-like functional substance is a rabbit interferon and / or interferon-like functional substance; when it is a mouse, the interferon and / or interferon-like functional substance is a mouse interferon and / or interferon-like functional substance;When the animal is a rat, the interferon and / or interferon-like functional substance is a rat interferon and / or interferon-like functional substance; when the animal is a camel, the interferon and / or interferon-like functional substance is a camel interferon and / or interferon-like functional substance; when the animal is a dromedary, the interferon and / or interferon-like functional substance is a dromedary interferon and / or interferon-like functional substance; when the animal is a llama, the interferon and / or interferon-like functional substance is a llama interferon and / or interferon-like functional substance; when the animal is an alpaca, the interferon and / or interferon-like functional substance is an alpaca interferon and / or interferon-like functional substance; when the animal is a dog, the interferon and / or interferon-like functional substance is a canine interferon and / or interferon-like functional substance; and / or when the animal is a cat, the interferon and / or interferon-like functional substance is a feline interferon and / or interferon-like functional substance.

[0217] Preferably, the interferon and / or interferon-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is not an interferon and / or interferon-like functional substance endogenous to the subject. In other words, preferably, the interferon and / or interferon-like functional substance is not an interferon and / or interferon-like functional substance isolated from the subject's body, i.e., from the individual subject to be treated or prevented.

[0218] Preferably, the interferon and / or interferon-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may be, and preferably is, a recombinant interferon and / or interferon-like functional substance produced by any recombinant expression technique known to those skilled in the art, a chemically synthesized interferon and / or interferon-like functional substance synthesized by any production technique known to those skilled in the art, an artificially produced interferon and / or interferon-like functional substance produced by any production technique known to those skilled in the art, a naturally occurring interferon and / or interferon-like functional substance obtained from a natural source such as an animal or human, or any combination thereof. More preferably, the interferon and / or interferon-like functional substance is a recombinant interferon and / or interferon-like functional substance, a chemically synthesized interferon and / or interferon-like functional substance, an artificially produced interferon and / or interferon-like functional substance, or any combination thereof, and even more preferably, a recombinant interferon and / or interferon-like functional substance.

[0219] Furthermore, the interferon and / or interferon-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may be derivatized, stabilized, fused to other proteins or peptides, conjugated with a polymer, contain amino acid analogs or artificial amino acids, covalently or non-covalently modified, e.g., by post-translational modification, e.g., glycosylated or methylated, and / or oligomerized, e.g., dimerized or trimerized, or not, so long as it is capable of and / or acts on PBMCs. More preferably, the modification pattern and / or oligomerization state is similar or identical to a peptide, protein or a fragment of any of these that occurs naturally in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0220] Preferably, in any of the embodiments described herein, the interferon and / or interferon-like functional substance is administered in a sufficiently low amount to avoid a systemic increase in the concentration of interferon and / or interferon-like functional substance in the subject's body. This is intended to avoid the generation of increased concentrations of interferon and / or interferon-like functional substance at the site of inflammation, such as an inflamed joint. As already mentioned above, for example, naive T cells can mature into cytotoxic cells that can function as pro-inflammatory cells in the presence of antigens / autoantigens / allergens. This reduces, cancels, or even reverses the beneficial effects achieved by the present invention, particularly the anti-inflammatory effects of the regulatory T cells and / or helper T cells, or their subsets, that may be generated.

[0221] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interferon and / or interferon-like functional substance is administered in an amount that does not cause a systemic increase, more preferably an effective systemic increase, in the concentration of the interferon and / or interferon-like functional substance in the subject, preferably the subject's blood, and / or causes a systemic increase in the concentration of the interferon and / or interferon-like functional substance. Preferably, the interferon and / or interferon-like functional substance is administered in an amount that is sufficiently low so that the systemic increase is ineffective.

[0222] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interferon and / or interferon-like functional substance is administered in an amount that causes a local increase, preferably an effective local increase, in the concentration of the interferon and / or interferon-like functional substance in the subject, preferably in the skin tissue of the subject. Skin tissue is preferred because, unlike administration into the blood, there is no or less washout and dilution of the interferon and / or interferon-like functional substance.

[0223] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the production of an increased concentration, preferably an effective increased concentration, of the administered interferon and / or interferon-like functional substance is only local and not systemic in the subject.

[0224] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interferon and / or interferon-like functional substance is administered in an amount that does not cause systemic activation, preferably effective systemic activation, of the individual receptors of the interferon and / or interferon-like functional substance, and / or does not cause systemic production, preferably effective systemic production, of the interferon and / or interferon-like functional substance, preferably in the subject.

[0225] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interferon and / or interferon-like functional substance is administered in an amount that causes local activation, preferably effective local activation, of individual receptors for the interferon and / or interferon-like functional substance, preferably in the subject, and / or causes local production, preferably effective local production, of the interferon and / or interferon-like functional substance. Preferably, the activation and / or production, more preferably effective production and / or effective activation, is only local and not systemic in the subject.

[0226] Preferably, the interferon-like functional substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or the immunomodulatory substance of steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is an interferon and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof, and / or is an IFN-γ-like functional substance.

[0227] Preferably, the interferon as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is IFN-γ.

[0228] More preferably, the immunomodulatory substance for use in accordance with the present invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits is IFN-γ and / or derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts of any of these, even more preferably IFN-γ.

[0229] The expression "interleukin-like functional substance" or "interleukin-like functional substances", when referred to in any of the embodiments described herein, may be, and preferably is, any substance that exerts an effect similar to or identical to that of an interleukin in the body of a subject when administered thereto. Interleukin-like functional substances can include precursors, prodrugs and propeptides of such substances that are not normally active as such, i.e., do not have immunomodulatory activity, but which are converted into an active interleukin-like functional substance when used in accordance with the present invention. Preferably, therefore, it is any substance, molecule, peptide, protein, protein analogue, protein variant, derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or any derivative, fragment and / or pharmaceutically acceptable salt of any of these. Accordingly, an interleukin-like functional substance is: - activates or is capable of activating individual interleukin receptors of cells, which may be, for example, receptors of PBMCs; and / or - causing or causing or capable of causing or causing the production of interleukins and / or interleukin-like functional substances It is possible.

[0230] More preferably, the interleukin-like functional substance activates or is capable of activating an individual interleukin receptor. The activation or ability to activate an individual interleukin receptor may be direct and / or indirect.

[0231] Preferably, the interleukin-like functional substance activates or is capable of activating individual interleukin receptors in the skin of a subject. The interleukin-like functional substance can be any naturally occurring or artificial interleukin-like functional substance, as long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and is particularly capable of activating individual interleukin receptors. Preferably, the interleukin-like functional substance is known to those skilled in the art as of the filing date of the present application.

[0232] More preferably, the interleukin-like functional substance is any peptide, protein, protein analog, protein variant or any derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt of any of these.

[0233] In a preferred embodiment, the interleukin-like functional substance may be, inter alia, an interleukin and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof, as detailed below.

[0234] More preferably, the interleukin-like functional substance is an interleukin and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof.

[0235] The expression "interleukin" or "interleukins" when referred to in any of the embodiments described herein should preferably be interpreted broadly. Typically, an interleukin activates or is capable of activating individual interleukin receptors on cells. The interleukin receptors may be, for example, receptors on PBMCs. Preferably, the activation or ability to activate is within the skin of a subject, more preferably in a locally effective amount within the skin of a subject, and even more preferably not in a systemically effective amount within the body of a subject. Preferably, the interleukin may be any type of interleukin known to those skilled in the art. Furthermore, the present invention encompasses the use or medical use of precursors, prodrugs, and propeptides of such interleukins that are not normally active as such, i.e., do not have immunomodulatory activity, but are converted into actual active interleukins upon use in accordance with the present invention. Thus, they can be used in the methods or medical uses described herein, or in the preparation of pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices, and / or kits as described herein.

[0236] Preferably, the interleukin may be any peptide, protein, protein analogue, protein variant and / or any derivative or pharmaceutically acceptable salt of any of these.

[0237] The interleukin does not necessarily have to be derived from or identical to an interleukin of the same genus and / or species to which the subject belongs, but can be any naturally occurring or artificial interleukin, so long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and in particular is capable of activating individual interleukin receptors. Preferably, the biological activity of the interleukin and / or interleukin-like functional substance is sufficient to achieve treatment and / or prevention of an inflammatory, immunological and / or autoimmune disease, preferably in the subject.

[0238] Interleukins and / or interleukin-like functional agents typically act on cells by binding to and activating individual interleukin receptors on the cells. Activation of the individual receptors therefore typically results in the cellular effects as described above for immunomodulatory agents. Therefore, any embodiment referred to herein for immunomodulatory agents in relation to their effects on cells such as PBMCs is independently applicable mutatis mutandis to interleukins and interleukin-like functional agents.

[0239] The activation or ability to activate individual interleukin receptors by interleukins and / or interleukin-like functional substances can be direct and / or indirect.

[0240] Unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances set forth above are applicable mutatis mutandis to interleukins and / or interleukin-like functional substances independently. In particular, unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances with respect to activating or being capable of activating individual interleukin receptors "directly" and "indirectly" are applicable mutatis mutandis to interleukins and / or interleukin-like functional substances independently.

[0241] Preferably, the interleukin and / or interleukin-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is capable of and / or acts on PBMCs by attracting, proliferating, differentiating and / or maturing, even more preferably by proliferating, differentiating and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the interleukin and / or interleukin-like functional substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the interleukin and / or interleukin-like functional substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the interleukin and / or interleukin-like functional substance is capable of differentiating and / or maturing PBMCs and / or causes the differentiation and / or maturation of PBMCs. Preferably, the PBMCs are naive PBMCs, more preferably lymphocytes, even more preferably T cells and / or B cells, also more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0242] More preferably, the interleukin and / or interleukin-like functional substance is capable of and / or does act directly and / or indirectly on PBMCs.

[0243] More preferably, the interleukin and / or interleukin-like functional substance is capable of and / or acts directly and / or indirectly on PBMCs in the subject, more preferably in the skin of the subject, as defined in any of the embodiments according to the present invention.

[0244] Even more preferably, the interleukin and / or interleukin-like functional substance is capable of and / or causes direct proliferation, differentiation and / or maturation of naive T cells in the subject, more preferably in the skin of the subject, as defined in any of the embodiments according to the present invention.

[0245] Unless otherwise stated, the descriptions and definitions of immunomodulatory substances set forth above are applicable mutatis mutandis to interleukins and / or interleukin-like functional substances, independently. In particular, unless otherwise stated, the descriptions and definitions of immunomodulatory substances that act or are capable of acting "directly" and "indirectly" on PBMCs are applicable mutatis mutandis to interleukins and / or interleukin-like functional substances, independently.

[0246] Preferably, the interleukin and / or interleukin-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is similar or identical, preferably identical, to any interleukin and / or interleukin-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body, more preferably a subject as defined in any of the embodiments according to the present invention. More preferably, the interleukin and / or interleukin-like functional substance is similar or identical, preferably identical, to any peptide, protein or fragment of any of these of an interleukin and / or interleukin-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0247] More preferably, the interleukin and / or interleukin-like functional agent has 70% or more, even more preferably 85% or more, also more preferably 90% or more, even more preferably 95% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more and up to 100% amino acid sequence identity to any peptide, protein, or fragment of any of these, of an interleukin and / or interleukin-like functional agent that occurs naturally in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably in a subject as defined in any of the embodiments according to the present invention. Preferably, the amino acid sequence identity includes amino acid residue substitutions, insertions and / or deletions relative to the naturally occurring peptide, protein, or fragment of any of these. Preferably, the total number of substitutions, insertions, and / or deletions of amino acid residues, or the total number of substitutions, insertions, and / or deletions combined, is 60 or less, more preferably 40 or less, even more preferably 20 or less, still more preferably 12 or less, still more preferably 8 or less, even more preferably 4 or less, still more preferably 2 or less and zero or more, and even more preferably zero.

[0248] Even more preferably, the interleukin and / or interleukin-like functional substance is identical to, or refers to amino acid sequence identity with, an endogenous immunomodulatory substance of the same genus and / or species to which the subject belongs. The expression "identical" typically means in this particular context that the interleukin and / or interleukin-like functional substance is identical to, an interleukin and / or interleukin-like functional substance of the same genus and / or species to which the subject belongs, with respect to its primary, secondary, tertiary and quaternary protein structure, and more preferably also taking into account modification patterns, in particular glycosylation.

[0249] Preferably, the interleukin and / or interleukin-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is derived from an individual belonging to the same genus and / or species as the subject or is identical to the interleukin and / or interleukin-like functional substance of the same genus and / or species to which the subject belongs. For example, if the subject is a human, the interleukin and / or interleukin-like functional substance is a human interleukin and / or interleukin-like functional substance; if the subject is a cow, the interleukin and / or interleukin-like functional substance is a bovine interleukin and / or interleukin-like functional substance; if the subject is a horse, the interleukin and / or interleukin-like functional substance is an equine interleukin and / or interleukin-like functional substance; if the subject is a donkey, the interleukin and / or interleukin-like functional substance is a donkey interleukin and / or interleukin-like functional substance; if the subject is an elephant, the interleukin and / or interleukin-like functional substance is an elephant interleukin and / or interleukin-like functional substance. when it is a sheep, the interleukin and / or interleukin-like functional substance is a sheep interleukin and / or interleukin-like functional substance; when it is a goat, the interleukin and / or interleukin-like functional substance is a goat interleukin and / or interleukin-like functional substance; when it is a pig, the interleukin and / or interleukin-like functional substance is a pig interleukin and / or interleukin-like functional substance; when it is a rabbit, the interleukin and / or interleukin-like functional substance is a rabbit interleukin and / or interleukin-like functional substance; when it is a mouse, the interleukin and / or interleukin-like functional substance is a mouse interleukin and / or interleukin-like functional substance;When the animal is a rat, the interleukin and / or interleukin-like functional substance is a rat interleukin and / or interleukin-like functional substance; when the animal is a camel, the interleukin and / or interleukin-like functional substance is a camel interleukin and / or interleukin-like functional substance; when the animal is a dromedary, the interleukin and / or interleukin-like functional substance is a dromedary interleukin and / or interleukin-like functional substance; when the animal is a llama, the interleukin and / or interleukin-like functional substance is a llama interleukin and / or interleukin-like functional substance; when the animal is an alpaca, the interleukin and / or interleukin-like functional substance is an alpaca interleukin and / or interleukin-like functional substance; when the animal is a dog, the interleukin and / or interleukin-like functional substance is a canine interleukin and / or interleukin-like functional substance; and / or when the animal is a cat, the interleukin and / or interleukin-like functional substance is a feline interleukin and / or interleukin-like functional substance.

[0250] Preferably, the interleukin and / or interleukin-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is not an interleukin and / or interleukin-like functional substance endogenous to the subject. In other words, preferably, the interleukin and / or interleukin-like functional substance is not an interleukin and / or interleukin-like functional substance isolated from the subject's body, i.e. from the individual subject to be treated or prevented.

[0251] Preferably, the interleukin and / or interleukin-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may be, and preferably is, a recombinant interleukin and / or interleukin-like functional substance produced by any recombinant expression technique known to those skilled in the art, a chemically synthesized interleukin and / or interleukin-like functional substance synthesized by any production technique known to those skilled in the art, an artificially produced interleukin and / or interleukin-like functional substance produced by any production technique known to those skilled in the art, a naturally occurring interleukin and / or interleukin-like functional substance obtained from a natural source such as an animal or a human, or any combination thereof. More preferably, the interleukin and / or interleukin-like functional substance is a recombinant interleukin and / or interleukin-like functional substance, a chemically synthesized interleukin and / or interleukin-like functional substance, an artificially produced interleukin and / or interleukin-like functional substance or any combination thereof, and even more preferably, a recombinant interleukin and / or interleukin-like functional substance.

[0252] Furthermore, the interleukin and / or interleukin-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may or may not be derivatized, stabilized, fused to other proteins or peptides, conjugated with polymers, contain amino acid analogues or artificial amino acids, covalently or non-covalently modified, e.g. by post-translational modification, e.g. glycosylated or methylated, and / or oligomerized, e.g. dimerized or trimerized, as long as it is capable of and / or acts on PBMCs. More preferably, the modification pattern and / or oligomerization state is similar or identical to a peptide, protein or a fragment of any of these that occurs naturally in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0253] Preferably, in any of the embodiments described herein, the interleukin and / or interleukin-like functional substance is administered in a sufficiently low amount to avoid a systemic increase in the concentration of the interleukin and / or interleukin-like functional substance in the subject's body. This avoids the generation of increased concentrations of the interleukin and / or interleukin-like functional substance at the site of inflammation, such as an inflamed joint. As already mentioned above, for example, naive T cells can mature into cytotoxic cells that can function as pro-inflammatory cells in the presence of antigens / autoantigens / allergens. This reduces, cancels, or even reverses the beneficial effects achieved by the present invention, particularly the anti-inflammatory effects of the regulatory T cells and / or helper T cells, or subsets thereof, that may be generated.

[0254] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interleukin and / or interleukin-like functional substance is administered in an amount that does not cause a systemic increase, more preferably an effective systemic increase, in the concentration of the interleukin and / or interleukin-like functional substance in the subject, preferably the blood of the subject, and / or that causes a systemic increase in the concentration of the interleukin and / or interleukin-like functional substance. Preferably, the interleukin and / or interleukin-like functional substance is administered in an amount that is sufficiently low so that the systemic increase is ineffective.

[0255] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interleukin and / or interleukin-like functional substance is administered in an amount that causes a local increase, preferably an effective local increase, in the concentration of the interleukin and / or interleukin-like functional substance in the subject, preferably in the skin tissue of the subject. Skin tissue is preferred because, unlike administration into the blood, there is no or less washout and dilution of the interleukin and / or interleukin-like functional substance.

[0256] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the production of an increased concentration, preferably an effective increased concentration, of the administered interleukin and / or interleukin-like functional substance is only local and not systemic in the subject.

[0257] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interleukin and / or interleukin-like functional substance is administered in an amount that does not cause systemic activation, preferably effective systemic activation, of the individual receptors for the interleukin and / or interleukin-like functional substance, and / or does not cause systemic production, preferably effective systemic production, of the interleukin and / or interleukin-like functional substance, preferably in the subject.

[0258] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the interleukin and / or interleukin-like functional substance is administered in an amount that causes local activation, preferably effective local activation, of individual receptors for the interleukin and / or interleukin-like functional substance, and / or causes local production, preferably effective local production, of the interleukin and / or interleukin-like functional substance, preferably in the subject. Preferably, the activation and / or production, more preferably effective production and / or effective activation, is only local and not systemic in the subject.

[0259] Preferably, the interleukin-like functional substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or the immunomodulatory substance of steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is an interleukin and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof, and / or is an IL-2-like functional substance or an IL-4-like functional substance.

[0260] Preferably, the interleukin as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is IL-2 and / or IL-4.

[0261] More preferably, the immunomodulatory substance for use in accordance with the present invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits is IL-2 and / or IL-4 and / or derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts of any of these, even more preferably IL-2 and / or IL-4.

[0262] The expression "neurotrophin-like functional substance" or "neurotrophin-like functional substances" as used in any of the embodiments described herein may refer to any substance, preferably any substance, that exerts an effect similar to or identical to that of a neurotrophin in the body of a subject when administered thereto. Neurotrophin-like functional substances can include precursors, prodrugs, and propeptides of such substances that are not normally active in themselves, i.e., do not have immunomodulatory activity, but are converted into an active neurotrophin-like functional substance when used in accordance with the present invention. Therefore, preferably, it is any substance, molecule, peptide, protein, protein analog, protein variant, derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, and / or any derivative, fragment, and / or pharmaceutically acceptable salt of any of these. Thus, a neurotrophin-like functional substance is: - activating or capable of activating individual neurotrophic factor receptors of cells, which may be, for example, receptors of PBMCs; and / or - causing or inducing or capable of causing or inducing the production of neurotrophic factors and / or neurotrophic factor-like functional substances It is possible.

[0263] More preferably, the neurotrophic factor-like functional substance activates or is capable of activating individual neurotrophic factor receptors. The activation or ability to activate individual neurotrophic factor receptors can be direct and / or indirect.

[0264] Preferably, the neurotrophic factor-like functional substance activates or is capable of activating individual neurotrophic factor receptors in the skin of a subject. The neurotrophic factor-like functional substance can be any naturally occurring or artificial neurotrophic factor-like functional substance, as long as it has sufficient biological activity, i.e., effective cross-reactivity in a subject, and is capable of activating individual neurotrophic factor receptors in particular. Preferably, the neurotrophic factor-like functional substance is known to those skilled in the art as of the filing date of the present application.

[0265] More preferably, the neurotrophic factor-like functional substance is any peptide, protein, protein analog, protein variant, or any derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, and / or pharmaceutically acceptable salt thereof.

[0266] In a preferred embodiment, the neurotrophic factor-like functional substance may be, inter alia, a neurotrophic factor and / or its derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts thereof, as detailed below.

[0267] More preferably, the neurotrophic factor-like functional substance is a neurotrophic factor and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof.

[0268] The expression "neurotrophic factor" or "neurotrophic factors" when referred to in any of the embodiments described herein should preferably be interpreted broadly. Typically, a neurotrophic factor activates or is capable of activating individual neurotrophic factor receptors on cells. The neurotrophic factor receptors may be, for example, receptors on PBMCs. Preferably, the activation or ability to activate is within the skin of a subject, more preferably in a locally effective amount within the skin of a subject, and even more preferably not in a systemically effective amount within the body of a subject. Preferably, the neurotrophic factor may be any type of neurotrophic factor known to those skilled in the art. Furthermore, the present invention encompasses the use or medical use of precursors, prodrugs, and propeptides of such neurotrophic factors that are not normally active as such, i.e., do not have immunomodulatory activity, but are converted into actual active neurotrophic factors upon use in accordance with the present invention. Therefore, they can be used in the methods or medical uses described herein, or in the preparation of pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices, and / or kits described herein.

[0269] Preferably, the neurotrophic factor may be any peptide, protein, protein analogue, protein variant and / or any derivative or pharmaceutically acceptable salt of any of these.

[0270] The neurotrophic factor does not necessarily have to be derived from or identical to a neurotrophic factor of the same genus and / or species to which the subject belongs, but can be any naturally occurring or artificial neurotrophic factor, as long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and is capable of activating individual neurotrophic factor receptors in particular. Preferably, the biological activity of the neurotrophic factor and / or neurotrophic factor-like functional substance is sufficient to achieve treatment and / or prevention of inflammatory, immunological, and / or autoimmune diseases, preferably in the subject.

[0271] Neurotrophic factors and / or neurotrophic factor-like functional substances typically act on cells by binding to and activating individual neurotrophic factor receptors on the cells. Thus, activation of the individual receptors typically results in the cellular effects described above for immunomodulatory substances. Thus, any embodiments referred to herein for immunomodulatory substances in relation to their effects on cells such as PBMCs are independently applicable mutatis mutandis to neurotrophic factors and neurotrophic factor-like functional substances.

[0272] The activation or ability to activate individual neurotrophic factor receptors by neurotrophic factors and / or neurotrophic factor-like functional substances can be direct and / or indirect.

[0273] Unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances set forth above are independently applicable mutatis mutandis to neurotrophic factors and / or neurotrophic factor-like functional substances. In particular, unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances that "directly" and "indirectly" activate or are capable of activating individual neurotrophic factor receptors are independently applicable mutatis mutandis to neurotrophic factors and / or neurotrophic factor-like functional substances.

[0274] Preferably, the neurotrophic factors and / or neurotrophic factor-like functional substances for use according to the present invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits are capable of and / or act on PBMCs by attracting, proliferating, differentiating and / or maturing, even more preferably by proliferating, differentiating and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the neurotrophic factors and / or neurotrophic factor-like functional substances are capable of and / or cause PBMCs to attract, proliferate, differentiate and / or mature, and / or attract, proliferate, differentiate and / or mature, and / or cause PBMCs to mature. Even more preferably, the neurotrophic factors and / or neurotrophic factor-like functional substances are capable of and / or cause PBMCs to proliferate, differentiate and / or mature. Even more preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is capable of differentiating and / or maturing PBMCs and / or differentiates and / or matures PBMCs. Preferably, the PBMCs are naive PBMCs, more preferably lymphocytes, even more preferably T cells and / or B cells, also more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0275] More preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is capable of and / or does act directly and / or indirectly on PBMCs.

[0276] More preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is capable of and / or acts directly and / or indirectly on PBMCs within the subject, more preferably within the skin of the subject, as defined in any of the embodiments according to the present invention.

[0277] Even more preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is capable of and / or directly causes the proliferation, differentiation and / or maturation of naive T cells in the body of a subject, more preferably in the skin of a subject, as defined in any of the embodiments according to the present invention.

[0278] Unless otherwise stated, the descriptions and definitions of immunomodulatory substances set forth above are independently applicable mutatis mutandis to neurotrophic factors and / or neurotrophic factor-like functional substances. In particular, unless otherwise stated, the descriptions and definitions of immunomodulatory substances that act or are capable of acting "directly" and "indirectly" on PBMCs are independently applicable mutatis mutandis to neurotrophic factors and / or neurotrophic factor-like functional substances.

[0279] Preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is similar or identical, preferably identical, to any neurotrophic factor and / or neurotrophic factor-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body, more preferably a subject as defined in any of the embodiments according to the present invention. More preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is similar or identical, preferably identical, to any peptide, protein or fragment of any of these neurotrophic factors and / or neurotrophic factor-like functional substances naturally occurring in a vertebrate, preferably a human or mammalian body as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0280] More preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance has 70% or more, even more preferably 85% or more, also more preferably 90% or more, even more preferably 95% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more and 100% or less amino acid sequence identity to any peptide, protein, or fragment of any of these of a neurotrophic factor and / or neurotrophic factor-like functional substance naturally occurring in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably in a subject as defined in any of the embodiments according to the present invention. Preferably, the amino acid sequence identity includes substitutions, insertions, and / or deletions of amino acid residues relative to the naturally occurring peptide, protein, or fragment of any of these. Preferably, the total number of substitutions, insertions, and / or deletions of amino acid residues, or the total number of substitutions, insertions, and / or deletions combined, is 60 or less, more preferably 40 or less, even more preferably 20 or less, still more preferably 12 or less, still more preferably 8 or less, even more preferably 4 or less, still more preferably 2 or less and zero or more, and even more preferably zero.

[0281] Even more preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is identical to, or refers to amino acid sequence identity with, an endogenous immunomodulatory substance of the same genus and / or species to which the subject belongs. The expression "identical" typically means in this particular context that the neurotrophic factor and / or neurotrophic factor-like functional substance is identical to, the neurotrophic factor and / or neurotrophic factor-like functional substance of the same genus and / or species to which the subject belongs, with respect to its primary, secondary, tertiary and quaternary protein structure, and more preferably also taking into account modification patterns, in particular glycosylation.

[0282] Preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is derived from an individual belonging to the same genus and / or species as the subject, or is identical to the neurotrophic factor and / or neurotrophic factor-like functional substance of the same genus and / or species to which the subject belongs. For example, if the subject is a human, the neurotrophic factor and / or neurotrophic factor-like functional substance is a human neurotrophic factor and / or neurotrophic factor-like functional substance; if the subject is a cow, the neurotrophic factor and / or neurotrophic factor-like functional substance is a bovine neurotrophic factor and / or neurotrophic factor-like functional substance; if the subject is a horse, the neurotrophic factor and / or neurotrophic factor-like functional substance is an equine neurotrophic factor and / or neurotrophic factor-like functional substance; if the subject is a donkey, the neurotrophic factor and / or neurotrophic factor-like functional substance is a donkey neurotrophic factor and / or neurotrophic factor-like functional substance; if the subject is an elephant, the neurotrophic factor and / or neurotrophic factor-like functional substance is an elephant neurotrophic factor and / or neurotrophic factor-like functional substance; if the subject is a sheep, the neurotrophic factor and / or neurotrophic factor-like functional substance. the substance is a sheep neurotrophic factor and / or a neurotrophic factor-like functional substance; if the animal is a goat, the neurotrophic factor and / or a neurotrophic factor-like functional substance is a goat neurotrophic factor and / or a neurotrophic factor-like functional substance; if the animal is a pig, the neurotrophic factor and / or a neurotrophic factor-like functional substance is a porcine neurotrophic factor and / or a neurotrophic factor-like functional substance; if the animal is a rabbit, the neurotrophic factor and / or a neurotrophic factor-like functional substance is a rabbit neurotrophic factor and / or a neurotrophic factor-like functional substance; if the animal is a mouse, the neurotrophic factor and / or a neurotrophic factor-like functional substance is a mouse neurotrophic factor and / or a neurotrophic factor-like functional substance; if the animal is a rat, the neurotrophic factor and / or a neurotrophic factor-like functional substance is a rat neurotrophic factor and / or a neurotrophic factor-like functional substance;When the animal is a camel, the neurotrophic factor and / or neurotrophic factor-like functional substance is a camel neurotrophic factor and / or neurotrophic factor-like functional substance; when the animal is a dromedary, the neurotrophic factor and / or neurotrophic factor-like functional substance is a dromedary neurotrophic factor and / or neurotrophic factor-like functional substance; when the animal is a llama, the neurotrophic factor and / or neurotrophic factor-like functional substance is a llama neurotrophic factor and / or neurotrophic factor-like functional substance; when the animal is an alpaca, the neurotrophic factor and / or neurotrophic factor-like functional substance is an alpaca neurotrophic factor and / or neurotrophic factor-like functional substance; when the animal is a dog, the neurotrophic factor and / or neurotrophic factor-like functional substance is a dog neurotrophic factor and / or neurotrophic factor-like functional substance; and / or when the animal is a cat, the neurotrophic factor and / or neurotrophic factor-like functional substance is a feline neurotrophic factor and / or neurotrophic factor-like functional substance.

[0283] Preferably, the neurotrophic factors and / or neurotrophic factor-like functional substances for use according to the present invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits are not endogenous neurotrophic factors and / or neurotrophic factor-like functional substances of the subject. In other words, preferably, the neurotrophic factors and / or neurotrophic factor-like functional substances are not neurotrophic factors and / or neurotrophic factor-like functional substances isolated from the subject's body, i.e., from the individual subject to be treated or prevented.

[0284] Preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance for use according to the present invention and / or step (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may be, and preferably is, a recombinant neurotrophic factor and / or neurotrophic factor-like functional substance produced by any recombinant expression technology known to those skilled in the art, a chemically synthesized neurotrophic factor and / or neurotrophic factor-like functional substance synthesized by any production technology known to those skilled in the art, an artificially produced neurotrophic factor and / or neurotrophic factor-like functional substance produced by any production technology known to those skilled in the art, a naturally occurring neurotrophic factor and / or neurotrophic factor-like functional substance obtained from a natural source such as an animal or a human, or any combination thereof. More preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is a recombinant neurotrophic factor and / or neurotrophic factor-like functional substance, a chemically synthesized neurotrophic factor and / or neurotrophic factor-like functional substance, an artificially produced neurotrophic factor and / or neurotrophic factor-like functional substance, or any combination thereof, and even more preferably, a recombinant neurotrophic factor and / or neurotrophic factor-like functional substance.

[0285] Furthermore, the neurotrophic factors and / or neurotrophic factor-like functional substances for use according to the present invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits may be derivatized, stabilized, fused to other proteins or peptides, conjugated with polymers, contain amino acid analogs or artificial amino acids, covalently or non-covalently modified, e.g., by post-translational modification, e.g., glycosylated or methylated, and / or oligomerized, e.g., dimerized or trimerized, or not, so long as they are capable of and / or act on PBMCs. More preferably, the modification pattern and / or oligomerization state is similar or identical to a peptide, protein or a fragment of any of these that occurs naturally in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0286] Preferably, in any of the embodiments described herein, the neurotrophic factor and / or neurotrophic factor-like functional substance is administered in a sufficiently low amount to avoid a systemic increase in the concentration of the neurotrophic factor and / or neurotrophic factor-like functional substance in the subject's body. This is intended to avoid the generation of increased concentrations of the neurotrophic factor and / or neurotrophic factor-like functional substance at the site of inflammation, such as an inflamed joint. As already mentioned above, for example, naive T cells can mature into cytotoxic cells that can function as pro-inflammatory cells in the presence of antigens / autoantigens / allergens. This reduces, cancels, or even reverses the beneficial effects achieved by the present invention, particularly the anti-inflammatory effects of the regulatory T cells and / or helper T cells, or their subsets, that may be generated.

[0287] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the neurotrophic factor and / or neurotrophic factor-like functional substance is administered in an amount that does not cause a systemic increase, more preferably an effective systemic increase, in the concentration of the neurotrophic factor and / or neurotrophic factor-like functional substance in the subject, preferably the subject's blood, and / or that causes a systemic increase in the concentration of the neurotrophic factor and / or neurotrophic factor-like functional substance. Preferably, the neurotrophic factor and / or neurotrophic factor-like functional substance is administered in an amount that is sufficiently low so that the systemic increase is ineffective.

[0288] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the neurotrophic factor and / or neurotrophic factor-like functional substance is administered in an amount that causes a local increase, preferably an effective local increase, in the concentration of the neurotrophic factor and / or neurotrophic factor-like functional substance in the subject, preferably in the skin tissue of the subject. Skin tissue is preferred because, unlike administration into the blood, there is no or less washout and dilution of the neurotrophic factor and / or neurotrophic factor-like functional substance.

[0289] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the production of an increased concentration, preferably an effective increased concentration, of the administered neurotrophic factor and / or neurotrophic factor-like functional substance is only local and not systemic in the subject.

[0290] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the neurotrophic factor and / or neurotrophic factor-like functional substance is administered in an amount that does not cause systemic activation, preferably effective systemic activation, of the neurotrophic factor and / or neurotrophic factor-like functional substance's individual receptors, and / or does not cause systemic production, preferably effective systemic production, of the neurotrophic factor and / or neurotrophic factor-like functional substance, preferably in the subject.

[0291] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the neurotrophic factor and / or neurotrophic factor-like functional substance is administered in an amount that causes local activation, preferably effective local activation, of individual receptors for the neurotrophic factor and / or neurotrophic factor-like functional substance, preferably within the subject, and / or causes local production, preferably effective local production, of the neurotrophic factor and / or neurotrophic factor-like functional substance. Preferably, the activation and / or production, more preferably effective production and / or effective activation, is only local and not systemic in the subject.

[0292] Preferably, the neurotrophic factor-like functional substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or the immunomodulatory substance of steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is a neurotrophic factor, a BDNF-like functional substance and / or an NGF-like functional substance, more preferably a neurotrophic factor and / or a BDNF-like functional substance.

[0293] Preferably, the neurotrophic factor as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is BDNF and / or NGF (nerve growth factor), more preferably BDNF.

[0294] More preferably, the immunomodulatory substance for use in accordance with the present invention and / or steps (B), (B1) and / or (C) of the methods, pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices and / or kits is BDNF, NGF (nerve growth factor) and / or derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts of any of these, even more preferably BDNF.

[0295] A "skin conditioning agent" as referred to in any of the embodiments described herein, in particular a skin conditioning agent for use according to the present invention and / or a skin conditioning agent administered in step (A), may be, and preferably is, any type or kind of substance, composition or formulation suitable for altering the condition of the skin, in particular with respect to the amount of PBMCs, the dilation of capillaries in the skin, the amount of blood in the skin, sO2 in the skin, rHb in the skin, the temperature on the skin and / or redness on the skin.

[0296] More preferably, the skin conditioning agent is preferably: - accumulation of PBMCs in the skin, preferably any embodiment or definition thereof described under the summary statement "Further with respect to step (A-0) of any of the embodiments as described herein" is to be understood as being independently applicable mutatis mutandis; and / or - dilation of capillaries in the skin, preferably any embodiment or definition thereof described under the summary statement "Further with respect to step (A-1) of any of the embodiments as described herein" is to be understood as being independently applicable mutatis mutandis; and / or - an increase in blood volume in the skin, preferably, any embodiment or definition thereof set out under the summary statement "Further with respect to step (A-2) of any of the embodiments as described herein" is to be understood as being independently applicable mutatis mutandis; and / or - an increase in sO2 (oxygen saturation of hemoglobin) and / or an increase in rHb (relative hemoglobin) in the skin, preferably, any embodiment or definition thereof described under the summary statement "Further with respect to step (A-3) of any of the embodiments as described herein" should be understood to be independently applicable mutatis mutandis; and / or - a temperature increase on the skin, preferably any embodiment or definition thereof described under the summary statement "Further with respect to step (A-4) of any of the embodiments as described herein" is to be understood as being independently applicable mutatis mutandis; and / or - redness on the skin, preferably, any embodiment or definition thereof set forth under the summary statement "Further with respect to step (A-5) of any of the embodiments as described herein" is to be understood as being independently applicable mutatis mutandis. The term "aquatic plant" refers to any type or kind of substance, composition or preparation suitable for and / or resulting in

[0297] Even more preferably, the skin conditioning agent is suitable and / or sufficient to cause and / or result in the dilation of capillaries in the skin, an increase in blood volume in the skin, an increase in sO2 and / or rHb in the skin, and / or an increase in temperature on the skin. Even more preferably, the skin conditioning agent causes the dilation of capillaries in the skin, an increase in sO2 and / or rHb in the skin, and / or an increase in temperature on the skin. Even more preferably, the skin conditioning agent causes the dilation of capillaries in the skin, an increase in sO2 and / or rHb in the skin, and / or an increase in temperature on the skin.

[0298] More preferably, the skin conditioning agent does not cause an allergic reaction in the subject.

[0299] Preferably, the skin conditioning agent is any blood circulation enhancer, vasodilator, skin temperature enhancer, skin sO2 enhancer, and / or skin rHb enhancer. Examples of skin conditioning agents include nitrates, alpha-blockers, ACE inhibitors, ginkgo preparations such as ginkgo balm, calcium antagonists, vasodilators such as dihydralazine, minoxidil, dihydroergotoxine, nicotinic acid analogs, methylnicotinate, wormwood, capsaicin, and / or pentoxifylline, heating creams, vasodilator-containing creams, methylnicotinate-containing creams, particularly Kytta® Heating Balm (Kytta® Heating Balm containing methylnicotinate ["Kytta® Heating Balm" from P&G Health Germany GmbH, Germany, PZN 12358936]), or any combination thereof. Preferably, the skin conditioning agent comprises, preferably consists of, as active ingredients, a nitrate, an alpha blocker, an ACE inhibitor, a ginkgo preparation such as ginkgo balm, a calcium antagonist, a vasodilator such as dihydralazine, minoxidil, dihydroergotoxine, a nicotinic acid analogue, methyl nicotinate, wormwood, capsaicin, pentoxifylline, a vasodilator-containing cream, a methyl nicotinate-containing cream, Kytta® heating balm or any combination thereof, more preferably a methyl nicotinate-containing cream and / or methyl nicotinate, even more preferably Kytta® heating balm and / or methyl nicotinate.

[0300] Preferably, the skin conditioning agent is in the form of any of a pharmaceutical composition, an injectable dosage form, a topical dosage form, a medical device and / or a kit according to the present invention or as referred to in any of the embodiments described herein.

[0301] Preferably, the blood circulation enhancer is an agent suitable for and / or which increases the blood volume in the skin, i.e. a blood volume expander. Even more preferably, the blood circulation enhancer is a blood volume expander.

[0302] Expression: "[...] the method comprises: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8). and [...]" is the expression: "The method includes step (A), wherein step (A) (A-0) A step of causing accumulation of PBMCs (peripheral blood mononuclear cells) in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) causing an increase in blood volume in the skin of a subject; (A-3) increasing sO2 (oxygen saturation of hemoglobin) in the skin of the subject and / or increasing rHb (relative hemoglobin content) in the skin; (A-4) generating a temperature increase on the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the subject's skin; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method further comprises the step [...]" It should be understood that the terms "a", "b", "c", "d" and "e" are equivalent in meaning and can be used interchangeably.

[0303] As already mentioned above, the present invention provides an immunomodulatory and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: The method comprises: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering an immunomodulatory agent to the skin of the subject. or comprising, preferably consisting of, or The method comprises: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (C) administering an immunomodulatory agent to the skin of the subject. or comprising, preferably consisting of, or The method comprises: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). and a method for treating the skin conditioner comprising, and preferably consisting of, an immunomodulatory agent and / or a skin conditioning agent.

[0304] Preferably, the present invention relates to an immunomodulatory substance and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: Step (B) is carried out a second time as (B1), the method comprising: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering an immunomodulatory agent to the skin of the subject; and (B1) administering an immunomodulatory substance to the skin of the subject. wherein the immunomodulatory substance administered in step (B1) is different from the immunomodulatory substance administered in step (B). The present invention relates to an immunomodulatory substance and / or skin conditioning agent comprising, and preferably consisting of,

[0305] More preferably, the present invention relates to an immunomodulatory substance and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, the method comprising: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering an immunomodulatory agent to the skin of the subject; and (B1) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory substances administered in step (B), step (B1) and step (C) are different from each other. The present invention relates to an immunomodulatory substance and / or skin conditioning agent comprising, and preferably consisting of,

[0306] Even more preferably, the present invention relates to an immunomodulatory substance and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, the method comprising: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. a first set of steps comprising, and preferably consisting of, and (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B1) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. A second set of steps comprising, and preferably consisting of, wherein the immunomodulatory agent administered in step (B1) is different from the immunomodulatory agent administered in step (B); and a set of steps, wherein the immunomodulatory substance administered in step (C) is different from the immunomodulatory substances administered in step (B) and step (B1). The present invention relates to an immunomodulatory substance and / or skin conditioning agent comprising, and preferably consisting of,

[0307] Preferably, the immunomodulatory agents administered in each of steps (C) are the same or different, more preferably the same.

[0308] Unless otherwise stated, it should be understood that any embodiment of step (A) described herein is independently applicable to each of the steps (A). Thus, step (A) of the first set of steps may or may not be performed identically to step (A) of the second set of steps, e.g., with respect to the mode of administration of the skin conditioning agent, the concentration used, whether administered by topical application or injection, the location of the skin area on the patient's body, and / or the size of the skin area. More preferably, steps (A) are all performed by topical application or injection.

[0309] Unless otherwise stated, it should be understood that any embodiment of step (C) described herein is independently applicable to each of the steps (C). Thus, step (C) of the first set of steps may or may not be performed identically to step (C) of the second set of steps, e.g., with respect to the type of immunomodulatory substance, the concentration used, whether administered by topical application or injection, the size of the skin area, etc. More preferably, step (C) is performed identically. Thus, in step (C) of the first set of steps, for example, administration of the immunomodulatory substance can be applied by injection, while in step (C) of the second set of steps, administration by topical application can be used.

[0310] More preferably, the present invention relates to an immunomodulatory and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: The method comprises: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering an immunomodulatory agent to the skin of the subject. or comprising, preferably consisting of, or Even more preferably, the method comprises: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering an immunomodulatory agent to the skin of the subject; and (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). and a method for treating the skin conditioner comprising, and preferably consisting of, an immunomodulatory agent and / or a skin conditioning agent.

[0311] Therefore, more preferably, the immunomodulatory substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use according to the invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is: Cytokine-like functional substances; Even more preferably, an immune-related cytokine-like functional substance; Even more preferably, an interferon-like functional substance, an interleukin-like functional substance, and / or a neurotrophic factor-like functional substance; Even more preferably, an IFN-γ-like functional substance, an IL-4-like functional substance, a BDNF-like functional substance, and / or an IL-2-like functional substance; More preferably, an IFN-γ-like functional substance, an IL-4-like functional substance, and / or a BDNF-like functional substance; Furthermore, an IFN-γ-like functional substance, an IL-4-like functional substance and / or an IL-2-like functional substance, or an IL-4-like functional substance, a BDNF-like functional substance and / or an IL-2-like functional substance; Even more preferably, an IFN-γ-like functional substance and / or an IL-4-like functional substance; or an IL-4-like functional substance and / or a BDNF-like functional substance; Even more preferably, an IFN-γ-like functional substance and / or an IL-2-like functional substance; or an IL-4-like functional substance and / or a BDNF-like functional substance; More preferably, an IFN-γ-like functional substance; or an IL-4-like functional substance and / or a BDNF-like functional substance; or an IL-2-like functional substance. is.

[0312] Even more preferably, the immunomodulatory substance as referred to in any of the embodiments described herein, in particular the immunomodulatory substance for use in accordance with the invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit, is: cytokines; Also more preferably, immune-related cytokines; Even more preferably, interferons, interleukins and / or neurotrophic factors; More preferably, IFN-γ, IL-4, BDNF and / or IL-2; Even more preferably, IFN-γ, IL-4 and / or BDNF; Even more preferably, IFN-γ, IL-4 and / or IL-2; or IL-4, BDNF and / or IL-2; Even more preferably, IFN-γ and / or IL-4; or IL-4 and / or BDNF; More preferably, IFN-γ and / or IL-2; or IL-4 and / or BDNF; Even more preferably, IFN-γ; or IL-4 and / or BDNF; or IL-2, and / or derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts of any of these.

[0313] For purposes of brevity and clarity, the following embodiments are written out in full length only with respect to cytokines, interferons, interleukins, neurotrophic factors, IFN-γ, IL-4, BDNF and / or IL-2. Unless otherwise stated, with respect to cytokines, interferons, interleukins, neurotrophic factors, IFN-γ, IL-4, BDNF and / or IL-2, and in particular the following items: - steps (A) and (C); steps (A), (B) and (C), steps (A) and (B); steps (A) and (B), where step (B) is performed a second time as (B1); or a method comprising a first set of steps (A), (B) and (C) and a second set of steps (A), (B1) and (C); and / or - the specific inflammatory, immunological and / or autoimmune disease to be treated and / or prevented; and / or - Any combination of any of these With respect to the following paragraphs, it should be understood that any of the embodiments of the invention generally described herein can be applied mutatis mutandis independently to a cytokine-like functional substance, an interferon-like functional substance, an interleukin-like functional substance, a neurotrophic factor-like functional substance, an IFN-γ-like functional substance, an IL-2-like functional substance, an IL-4-like functional substance and / or a BDNF-like functional substance, and for this reason, where applicable, the term "cytokine" should be understood as a "cytokine-like functional substance," "interferon" should be understood as an "interferon-like functional substance," "interleukin" should be understood as an "interleukin-like functional substance," "neurotrophic factor" should be understood as a "neurotrophic factor-like functional substance," "IFN-γ" should be understood as an "IFN-γ-like functional substance," "IL-4" should be understood as an "IL-4-like functional substance," "BDNF" should be understood as a "BDNF-like functional substance," and "IL-2" should be understood as an "IL-2-like functional substance." Preferably, in one particular embodiment, all of such terms are replaced or all of such terms remain unchanged, however, not some are replaced and some are not. More preferred are embodiments that refer to cytokines, interferons, neurotrophic factors, interleukins, IFN-γ, IL-4, BDNF, IL-2, and / or derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs, and / or pharmaceutically acceptable salts thereof. Even more preferred are embodiments that refer to cytokines, interferons, neurotrophic factors, interleukins, IFN-γ, IL-4, BDNF, and / or IL-2.

[0314] Preferably, - the method comprises steps (A) and (C); - the immunomodulatory agent for use in accordance with the present invention is any of the immunomodulatory agents as described herein, including IL-2, preferably a cytokine including IL-2, more preferably an interferon including IL-2, a neurotrophic factor and / or an interleukin, even more preferably IL-2; and - the immunomodulatory agent in step (C) is IL-2; or - the method comprises steps (A), (B) and (C); - the immunomodulatory agent for use in accordance with the present invention is any of the immunomodulatory agents as described herein, including IL-2, preferably a cytokine including IL-2, more preferably an interferon including IL-2, a neurotrophic factor and / or an interleukin, even more preferably IL-2; - the immunomodulatory agent in step (B) is any of the immunomodulatory agents as described herein, except for IL-2; and - the immunomodulatory agent in step (C) is IL-2; or - the method comprises steps (A) and (B); - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or BDNF, preferably IFN-γ and / or IL-4; and - the immunomodulatory substance in step (B) is IFN-γ and / or IL-4, or IL-4 and / or BDNF; preferably IFN-γ, or IL-4 and / or BDNF; more preferably IFN-γ or IL-4, or or - the method comprises steps (A), (B) and (C); - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4, BDNF and / or IL-2; - the immunomodulatory substance in step (B) is IFN-γ and / or IL-4, or IL-4 and / or BDNF; preferably IFN-γ, or IL-4 and / or BDNF; more preferably IFN-γ or IL-4; and - in step (C) the immunomodulatory agent is IL-2.

[0315] Even more preferably, The method comprises steps (A), (B) and (C); - the immunomodulatory substance for use according to the invention is IFN-γ and / or IL-2; - the immunomodulatory agent in step (B) is IFN-γ; and - the immunomodulatory agent in step (C) is IL-2; or - the immunomodulatory substance for use according to the invention is IL-4 and / or IL-2; - the immunomodulatory agent in step (B) is IL-4; and - the immunomodulatory agent in step (C) is IL-2; Alternatively, the method comprises steps (A) and (B), and step (B) is performed a second time as (B1); - the immunomodulatory substance for use according to the invention is IFN-γ and / or IL-4; - the immunomodulatory agent in step (B) is IFN-γ; and - the immunomodulatory substance in step (B1) is IL-4, or - the immunomodulatory substance for use according to the invention is IL-4 and / or BDNF; - the immunomodulatory agent in step (B) is IL-4; and - the immunomodulatory substance in step (B1) is BDNF.

[0316] Also more preferred are embodiments in which the method comprises steps (A), (B) and (C).

[0317] Unless otherwise stated, it should be understood that any embodiment or definition described herein with respect to step (B) can be applied mutatis mutandis independently to step (B1) when mentioned in any of the embodiments described herein.

[0318] Even more preferably, the method comprises steps (A), (B), (B1) and (C); - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or IL-2; - in step (B) the immunomodulatory agent is IFN-γ; - the immunomodulatory agent in step (B1) is IL-4; and - in step (C) the immunomodulatory agent is IL-2; or - the immunomodulatory substance for use according to the invention is IL-4, BDNF and / or IL-2; - the immunomodulatory agent in step (B) is IL-4; - the immunomodulatory substance in step (B1) is BDNF; and - in step (C) the immunomodulatory agent is IL-2.

[0319] More preferably, - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or IL-2, and Here's how: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering IFN-γ to the skin of the subject; and (C) administering IL-2 to the skin of the subject. a first set of steps, including: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B1) administering IL-4 to the skin of the subject; and (C) administering IL-2 to the skin of the subject. The second set of steps, including Contains or or - the immunomodulatory substance for use according to the invention is IL-4, BDNF and / or IL-2, and Here's how: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering IL-4 to the skin of the subject; and (C) administering IL-2 to the skin of the subject. a first set of steps, including: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B1) administering BDNF to the skin of the subject; and (C) administering IL-2 to the skin of the subject. The second set of steps, including Includes.

[0320] In any of the embodiments described herein that include steps (A) and (B), Even more preferably, - the immunomodulatory substance for use according to the invention is an interferon, a neurotrophic factor and / or an interleukin; - the immunomodulatory substance in step (B) is an interferon, a neurotrophic factor and / or an interleukin; And even more preferably, - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or BDNF; and - the immunomodulatory substance in step (B) is IFN-γ, IL-4 and / or BDNF; More preferably, - the immunomodulatory substance for use according to the invention is IFN-γ and / or IL-4 or IL-4 and / or BDNF; and - the immunomodulatory substance in step (B) is IFN-γ and / or IL-4 or IL-4 and / or BDNF; Even more preferably, - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or BDNF; and - the immunomodulatory substance in step (B) is IFN-γ and / or IL-4 or IL-4 and / or BDNF; Even more preferably, - the immunomodulatory substance for use according to the invention is IFN-γ or IL-4; and - the immunomodulatory substance in step (B) is IFN-γ or IL-4.

[0321] In any of the embodiments described herein that include steps (A) and (C), Even more preferably, - the immunomodulatory substance for use according to the present invention is a cytokine; and - the immunomodulatory agent in step (C) is a cytokine; And even more preferably, - the immunomodulatory substance for use according to the present invention is an interleukin; and - the immunomodulatory agent in step (C) is an interleukin; More preferably, - the immunomodulatory substance for use according to the invention is IL-2; and - in step (C) the immunomodulatory agent is IL-2.

[0322] In any of the embodiments described herein that include steps (A), (B), and (C), Even more preferably, - the immunomodulatory agent for use in accordance with the present invention is any of the immunomodulatory agents as described herein, including IL-2 as described herein, more preferably a cytokine, including IL-2; - the immunomodulatory agent in step (B) is any of the immunomodulatory agents as described herein except IL-2, more preferably a cytokine except IL-2; and - the immunomodulatory agent in step (C) is IL-2; And even more preferably, - the immunomodulatory substance for use according to the invention is an interferon, including IL-2, a neurotrophic factor and / or an interleukin; - the immunomodulatory agent in step (B) is an interferon, a neurotrophic factor and / or an interleukin, excluding IL-2; and - the immunomodulatory agent in step (C) is IL-2; More preferably, - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4, BDNF and / or IL-2; - the immunomodulatory substance in step (B) is IFN-γ, IL-4 and / or BDNF, more preferably IFN-γ and / or IL-4 or IL-4 and / or BDNF; and - the immunomodulatory agent in step (C) is IL-2; Even more preferably, - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or IL-2, preferably IFN-γ and / or IL-2 or IL-4 and / or IL-2; - the immunomodulatory substance in step (B) is IFN-γ and / or IL-4, preferably IFN-γ or IL-4; and - in step (C) the immunomodulatory agent is IL-2.

[0323] All embodiments of the invention described herein relating to IFN-γ, preferably all embodiments referring to IFN-γ alone or in combination with either IL-4 and / or IL-2, In particular, in all embodiments where the immunomodulatory substance for use according to the invention comprises, preferably is, IFN-γ or IFN-γ in combination with IL-4 and / or IL-2, and where the immunomodulatory substance administered in step (B) comprises, preferably is, IFN-γ or IFN-γ and IL-4: Inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented include: - comprising, preferably consisting of, any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, excluding inflammatory diseases of the nervous system, preferably excluding multiple sclerosis, more preferably comprising, and preferably consisting of, arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease and / or Graves' disease, - Even more preferably comprising, and even more preferably consisting of, arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, Bechterew's disease and / or Graves' disease.

[0324] All embodiments of the invention described herein relating to BDNF, preferably all embodiments referring to BDNF alone or in combination with IL-4 and / or IL-2, In particular, in all embodiments where the immunomodulatory substance for use in accordance with the invention comprises, and preferably is, BDNF or BDNF in any combination with IL-4 and / or IL-2, and the immunomodulatory substance administered in step (B) comprises, and preferably is BDNF or BDNF and IL-4: Inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented include: - including, and preferably consisting of, inflammatory diseases of the nervous system; - More preferably, it comprises, even more preferably consists of, multiple sclerosis.

[0325] All embodiments of the invention described herein relating to IL-4, preferably all embodiments referring to IL-4 alone or in combination with BDNF and / or IL-2, In particular, in all embodiments where the immunomodulatory substance for use in accordance with the invention comprises, and preferably is, IL-4 or IL-4 in any combination with BDNF and / or IL-2, and the immunomodulatory substance administered in step (B) comprises, and preferably is IL-4 or IL-4 and BDNF: Inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented include: - comprising, preferably consisting of, any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, - preferably including, preferably consisting of, inflammatory diseases of the nervous system, - More preferably, it comprises, even more preferably consists of, multiple sclerosis.

[0326] All embodiments of the invention described herein relating to IL-2, preferably all embodiments referring to IL-2 alone or in combination with IFN-γ, BDNF and / or IL-4, In particular, in all embodiments where the immunomodulatory agent for use in accordance with the invention is any of the immunomodulatory agents as described herein, including IL-2 as disclosed herein, preferably a cytokine, including IL-2, more preferably an interferon, neurotrophic factor and / or interleukin, including IL-2, even more preferably IL-2 or IL-2 in any combination with IFN-γ, BDNF and / or IL-4, and the immunomodulatory agent administered in step (C) comprises IL-2, preferably IL-2; Inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented include: - In the case of IL-2, comprising, preferably consisting of, an inflammatory, immunological and / or autoimmune disease as described herein, - in the case of IL-2, either in combination with IFN-γ and / or IL-4, preferably in combination with IFN-γ, Preferably, it comprises, more preferably consists of, inflammatory, immunological and / or autoimmune diseases, excluding inflammatory diseases of the nervous system, excluding multiple sclerosis, More preferably, it comprises, and preferably consists of, arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease and / or Graves' disease, Even more preferably, it comprises, and more preferably consists of, arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, Bechterew's disease and / or Graves' disease, and / or - in the case of IL-2 in any combination with BDNF and / or IL-4, including, and preferably consisting of, inflammatory diseases of the nervous system; Preferably it comprises, preferably consists of, multiple sclerosis.

[0327] Therefore, and even more preferably, - the method comprises steps (A) and (C); - the immunomodulatory agent for use according to the present invention is any of the immunomodulatory agents as described herein, including IL-2, preferably cytokines including IL-2, more preferably interferons including IL-2, neurotrophic factors and / or interleukins, even more preferably IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein; and - in step (C) the immunomodulatory agent is IL-2; or - the method comprises steps (A), (B) and (C); - the immunomodulatory agent for use according to the present invention is any of the immunomodulatory agents as described herein, including IL-2, preferably cytokines including IL-2, more preferably interferons including IL-2, neurotrophic factors and / or interleukins, even more preferably IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein; - the immunomodulatory agent in step (B) is any of the immunomodulatory agents described herein except IL-2; and - in step (C) the immunomodulatory agent is IL-2; or - the method comprises steps (A) and (B); - the immunomodulatory substance for use according to the invention is IFN-γ and / or IL-4, preferably IFN-γ; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, excluding inflammatory diseases of the nervous system, preferably excluding multiple sclerosis, preferably arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease and / or Graves' disease, more preferably arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, Bechterew's disease and / or Graves' disease; and - the immunomodulatory substance in step (B) is IFN-γ and / or IL-4, preferably IFN-γ, or - the method comprises steps (A) and (B); - the immunomodulatory substance for use according to the invention is IL-4 and / or BDNF, preferably IL-4; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is an inflammatory disease of the nervous system, preferably multiple sclerosis; and - the immunomodulatory substance in step (B) is IL-4 and / or BDNF, preferably IL-4.

[0328] More preferably, The method comprises steps (A), (B) and (C); - the immunomodulatory substance for use according to the invention is IFN-γ and / or IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, excluding inflammatory diseases of the nervous system, preferably excluding multiple sclerosis, preferably arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease and / or Graves' disease, more preferably arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, Bechterew's disease and / or Graves' disease; - the immunomodulatory agent in step (B) is IFN-γ; and - in step (C) the immunomodulatory agent is IL-2; or - the immunomodulatory substance for use according to the invention is IL-4 and / or IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, preferably arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease, Graves' disease and / or multiple sclerosis, more preferably arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, Bechterew's disease, Graves' disease and / or multiple sclerosis; - the immunomodulatory agent in step (B) is IL-4; and - in step (C) the immunomodulatory agent is IL-2; Alternatively, the method comprises steps (A) and (B), and step (B) is performed a second time as (B1); - the immunomodulatory substance for use according to the invention is IFN-γ and / or IL-4; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, excluding inflammatory diseases of the nervous system, preferably excluding multiple sclerosis, preferably arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease and / or Graves' disease, more preferably arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, Bechterew's disease and / or Graves' disease; - the immunomodulatory agent in step (B) is IFN-γ; and - the immunomodulatory substance in step (B1) is IL-4, or - the immunomodulatory substance for use according to the invention is IL-4 and / or BDNF; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is an inflammatory disease of the nervous system, preferably multiple sclerosis; - the immunomodulatory agent in step (B) is IL-4; and - the immunomodulatory substance in step (B1) is BDNF.

[0329] Also more preferred are embodiments in which the method comprises steps (A), (B) and (C).

[0330] Even more preferably, the method comprises steps (A), (B), (B1) and (C); - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, excluding inflammatory diseases of the nervous system, preferably excluding multiple sclerosis, preferably arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease and / or Graves' disease, more preferably arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, Bechterew's disease and / or Graves' disease; - in step (B) the immunomodulatory agent is IFN-γ; - the immunomodulatory agent in step (B1) is IL-4; and - in step (C) the immunomodulatory agent is IL-2; or, - the immunomodulatory substance for use according to the invention is IL-4, BDNF and / or IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is an inflammatory disease of the nervous system, preferably multiple sclerosis; - in step (B) the immunomodulatory agent is IL-4; - the immunomodulatory substance in step (B1) is BDNF; and - in step (C) the immunomodulatory agent is IL-2.

[0331] Even more preferably, - the immunomodulatory substance for use according to the invention is IFN-γ, IL-4 and / or IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is any of the inflammatory, immunological and / or autoimmune diseases to be treated and / or prevented as described herein, excluding inflammatory diseases of the nervous system, preferably excluding multiple sclerosis, preferably arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease and / or Graves' disease, more preferably arthritis, synovitis, rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, Bechterew's disease and / or Graves' disease; and The method is: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering IFN-γ to the skin of the subject; and (C) administering IL-2 to the skin of the subject. a first set of steps, including: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B1) administering IL-4 to the skin of the subject; and (C) administering IL-2 to the skin of the subject. The second set of steps, including Contains or or - the immunomodulatory substance for use according to the invention is IL-4, BDNF and / or IL-2; - the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented is an inflammatory disease of the nervous system, preferably multiple sclerosis; and The method is: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B) administering IL-4 to the skin of the subject; and (C) administering IL-2 to the skin of the subject. a first set of steps, including: (A) selected from one or more of steps (A-0), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7) and / or (A-8); and (B1) administering BDNF to the skin of the subject; and (C) administering IL-2 to the skin of the subject. The second set of steps, including Includes.

[0332] For purposes of brevity and clarity, the above embodiments have been written out in full length only with respect to cytokines, interferons, interleukins, neurotrophic factors, IFN-γ, IL-4, BDNF, and / or IL-2. Unless otherwise stated, it should be understood that any of the preferred embodiments of the invention described herein with respect to cytokines, interferons, interleukins, neurotrophic factors, IFN-γ, IL-4, BDNF, and / or IL-2 can be applied mutatis mutandis independently to cytokine-like functional substances, interferon-like functional substances, interleukin-like functional substances, neurotrophic factor-like functional substances, IFN-γ-like functional substances, IL-2-like functional substances, IL-4-like functional substances, and / or BDNF-like functional substances, and for this reason, the term "cytokine" will be used where applicable. "In" should be understood as a "cytokine-like functional substance," "interferon" should be understood as an "interferon-like functional substance," "interleukin" should be understood as an "interleukin-like functional substance," "neurotrophic factor" should be understood as a "neurotrophic factor-like functional substance," "IFN-γ" should be understood as an "IFN-γ-like functional substance," "IL-4" should be understood as an "IL-4-like functional substance," "BDNF" should be understood as a "BDNF-like functional substance," and "IL-2" should be understood as an "IL-2-like functional substance." Preferably, in one particular embodiment, all of such terms are replaced or all of such terms remain unchanged, however, not some are replaced and some are not replaced. More preferred are embodiments that refer to cytokines, interferons, neurotrophic factors, interleukins, IFN-γ, IL-4, BDNF, IL-2, and / or derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs, and / or pharmaceutically acceptable salts thereof. Even more preferred are embodiments that refer to cytokines, interferons, neurotrophic factors, interleukins, IFN-γ, IL-4, BDNF, and / or IL-2.

[0333] The expression "IFN-γ-like functional substance" or "IFN-γ-like functional substances", when referred to in any of the embodiments described herein, may be, and preferably is, any substance that exerts an effect similar to or identical to IFN-γ in the body of a subject when administered thereto. IFN-γ-like functional substances can include precursors, prodrugs, and propeptides of such substances that are not normally active as such, i.e., do not have immunomodulatory activity, but are converted into an active IFN-γ-like functional substance when used in accordance with the present invention. Therefore, preferably, it is any substance, molecule, peptide, protein, protein analog, protein variant, derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, and / or any derivative, fragment, and / or pharmaceutically acceptable salt of any of these. Accordingly, an IFN-γ-like functional substance is: - activates or is capable of activating a particular IFN-γ receptor on the cell, which may be, for example, a receptor on PBMCs; and / or - causing or causing or capable of causing or causing the production of IFN-γ and / or IFN-γ-like functional substances It is possible.

[0334] More preferably, the IFN-γ-like functional substance activates or is capable of activating an individual IFN-γ receptor. The activation or ability to activate an individual IFN-γ receptor may be direct and / or indirect.

[0335] Preferably, the IFN-γ-like functional substance activates or is capable of activating an individual IFN-γ receptor in the skin of a subject. The IFN-γ-like functional substance can be any naturally occurring or artificial IFN-γ-like functional substance, so long as it has sufficient biological activity, i.e., effective cross-reactivity in a subject, and is particularly capable of activating an individual IFN-γ receptor. Preferably, the IFN-γ-like functional substance is known to those skilled in the art as of the filing date of the present application.

[0336] More preferably, the IFN-γ-like functional substance is any peptide, protein, protein analog, protein variant, or any derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, and / or pharmaceutically acceptable salt thereof.

[0337] In a preferred embodiment, the IFN-γ-like functional substance may be, inter alia, IFN-γ and / or its derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts thereof, as detailed below.

[0338] More preferably, the IFN-γ-like functional substance is IFN-γ and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof.

[0339] The expression "IFN-γ" should preferably be interpreted broadly when referred to in any of the embodiments described herein. Typically, IFN-γ activates or is capable of activating a specific IFN-γ receptor on a cell. The IFN-γ receptor may be, for example, a receptor on PBMCs. Preferably, the activation or ability to activate is within the skin of a subject, more preferably in a locally effective amount within the skin of a subject, and even more preferably not in a systemically effective amount within the body of a subject. Preferably, IFN-γ may be any type of IFN-γ known to those skilled in the art. Furthermore, the present invention encompasses the use or medical use of such IFN-γ precursors, prodrugs, and propeptides that are not normally active in themselves, i.e., do not have immunomodulatory activity, but are converted into active IFN-γ upon use in accordance with the present invention. Therefore, they can be used in the methods or medical uses described herein, or in the preparation of pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices, and / or kits described herein.

[0340] Preferably, the IFN-γ may be any peptide, protein, protein analogue, protein variant and / or any derivative or pharmaceutically acceptable salt of any of these.

[0341] The IFN-γ does not necessarily have to be derived from or identical to the IFN-γ of the same genus and / or species to which the subject belongs, but can be any naturally occurring or artificial IFN-γ, as long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and is capable of activating individual IFN-γ receptors in particular. Preferably, the biological activity of the IFN-γ and / or IFN-γ-like functional substance is sufficient to achieve treatment and / or prevention of an inflammatory disease, immunological disease, and / or autoimmune disease, preferably in the subject.

[0342] IFN-γ and / or IFN-γ-like functional agents typically act on cells by binding to and activating individual IFN-γ receptors on the cells. Activation of the individual receptors therefore typically results in the cellular effects as described above for immunomodulatory agents. Therefore, any embodiment referred to herein for immunomodulatory agents in relation to their effects on cells, such as PBMCs, is independently applicable mutatis mutandis to IFN-γ and IFN-γ-like functional agents.

[0343] The activation or ability to activate individual IFN-γ receptors by IFN-γ and / or IFN-γ-like functional substances may be direct and / or indirect.

[0344] Unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances set forth above are applicable mutatis mutandis to IFN-γ and / or IFN-γ-like functional substances independently. In particular, unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances that "directly" and "indirectly" activate or are capable of activating individual IFN-γ receptors are applicable mutatis mutandis to IFN-γ and / or IFN-γ-like functional substances independently.

[0345] Preferably, the IFN-γ and / or IFN-γ-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is capable of and / or acts on PBMCs by attracting, proliferating, differentiating and / or maturing, even more preferably by proliferating, differentiating and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the IFN-γ and / or IFN-γ-like functional substance is capable of and / or causes PBMCs to attract, proliferate, differentiate and / or mature. Even more preferably, the IFN-γ and / or IFN-γ-like functional substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the IFN-γ and / or IFN-γ-like functional substance is capable of differentiating and / or maturing PBMCs and / or differentiates and / or matures PBMCs. Preferably, the PBMCs are naive PBMCs, more preferably lymphocytes, even more preferably T cells and / or B cells, also more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0346] More preferably, the IFN-γ and / or IFN-γ-like functional substance is capable of and / or does act directly and / or indirectly on PBMCs.

[0347] More preferably, the IFN-γ and / or IFN-γ-like functional substance is capable of and / or acts directly and / or indirectly on PBMCs in the subject, more preferably in the skin of the subject, as defined in any of the embodiments according to the present invention.

[0348] Even more preferably, the IFN-γ and / or IFN-γ-like functional substance is capable of and / or directly causes the proliferation, differentiation and / or maturation of naive T cells in a subject, more preferably in the skin of a subject, as defined in any of the embodiments according to the present invention.

[0349] Unless otherwise stated, the descriptions and definitions of immunomodulatory substances set forth above are applicable mutatis mutandis to IFN-γ and / or IFN-γ-like functional substances, independently. In particular, unless otherwise stated, the descriptions and definitions of immunomodulatory substances that act or are capable of acting "directly" and "indirectly" on PBMCs are applicable mutatis mutandis to IFN-γ and / or IFN-γ-like functional substances, independently.

[0350] Preferably, the IFN-γ and / or IFN-γ-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is similar or identical, preferably identical, to any IFN-γ and / or IFN-γ-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body, more preferably a subject as defined in any of the embodiments according to the present invention. More preferably, the IFN-γ and / or IFN-γ-like functional substance is similar or identical, preferably identical, to any peptide, protein or fragment of any of these of IFN-γ and / or IFN-γ-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0351] More preferably, the IFN-γ and / or IFN-γ-like functional substance has 70% or more, even more preferably 85% or more, even more preferably 90% or more, even more preferably 95% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more and 100% or less amino acid sequence identity to any peptide, protein, or fragment of any of these of IFN-γ and / or IFN-γ-like functional substance naturally occurring in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably a subject as defined in any of the embodiments according to the present invention. Preferably, the amino acid sequence identity includes substitutions, insertions, and / or deletions of amino acid residues relative to the naturally occurring peptide, protein, or fragment of any of these. Preferably, the amino acid sequence identity refers to the amino acid sequence of SEQ ID NO: 1, and more preferably, the subject is a human.

[0352] Preferably, the total number of substitutions, insertions and / or deletions of amino acid residues or the total number of substitutions, insertions and / or deletions combined is preferably 60 or less, more preferably 40 or less, even more preferably 20 or less, still more preferably 12 or less, still more preferably 8 or less, even more preferably 4 or less, still more preferably 2 or less and zero or more, and still more preferably zero, with reference to the amino acid sequence of SEQ ID NO: 1; in this case, more preferably, the subject is a human.

[0353] Even more preferably, the IFN-γ and / or IFN-γ-like functional substance is identical to, or refers to amino acid sequence identity with, an endogenous immunomodulatory substance of the same genus and / or species to which the subject belongs. The expression "identical" typically means in this particular context that the IFN-γ and / or IFN-γ-like functional substance is identical to, the IFN-γ and / or IFN-γ-like functional substance of the same genus and / or species to which the subject belongs, with respect to its primary, secondary, tertiary and quaternary protein structure, and more preferably also taking into account modification patterns, in particular glycosylation.

[0354] Preferably, the IFN-γ and / or IFN-γ-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is derived from an individual belonging to the same genus and / or biological species as the subject, or is identical to the IFN-γ and / or IFN-γ-like functional substance of the same genus and / or biological species to which the subject belongs. For example, if the subject is a human, the IFN-γ and / or IFN-γ-like functional substance is a human IFN-γ and / or IFN-γ-like functional substance, more preferably a human IFN-γ and / or IFN-γ-like functional substance that preferably comprises, and even more preferably consists of, the amino acid sequence of SEQ ID NO: 1 as an effective amino acid sequence; if the subject is a bovine, the IFN-γ and / or IFN-γ-like functional substance is a bovine IFN-γ and / or IFN-γ-like functional substance; if the subject is a horse, the IFN-γ and / or IFN-γ-like functional substance is an equine IFN-γ and / or IFN-γ-like functional substance; if the subject is a donkey, the IFN-γ and / or IFN-γ-like functional substance is a donkey IFN-γ and / or IFN-γ-like functional substance; if the subject is an elephant, the IFN-γ and and / or the IFN-γ-like functional substance is elephant IFN-γ and / or IFN-γ-like functional substance; if it is a sheep, the IFN-γ and / or IFN-γ-like functional substance is ovine IFN-γ and / or IFN-γ-like functional substance; if it is a goat, the IFN-γ and / or IFN-γ-like functional substance is caprine IFN-γ and / or IFN-γ-like functional substance; if it is a pig, the IFN-γ and / or IFN-γ-like functional substance is porcine IFN-γ and / or IFN-γ-like functional substance; if it is a rabbit, the IFN-γ and / or IFN-γ-like functional substance is rabbit IFN-γ and / or IFN-γ-like functional substance; if it is a mouse, the IFN-γ and / or IFN-γ-like functional substance is mouse IFN-γ and / or IFN-γ-like functional substance;When the animal is a rat, the IFN-γ and / or IFN-γ-like functional substance is a rat IFN-γ and / or IFN-γ-like functional substance; when the animal is a camel, the IFN-γ and / or IFN-γ-like functional substance is a camel IFN-γ and / or IFN-γ-like functional substance; when the animal is a dromedary, the IFN-γ and / or IFN-γ-like functional substance is a dromedary IFN-γ and / or IFN-γ-like functional substance; when the animal is a llama, the IFN-γ and / or IFN-γ-like functional substance is a llama. The substance is a llama IFN-γ and / or IFN-γ-like functional substance; if it is an alpaca, the IFN-γ and / or IFN-γ-like functional substance is an alpaca IFN-γ and / or IFN-γ-like functional substance; if it is a dog, the IFN-γ and / or IFN-γ-like functional substance is a canine IFN-γ and / or IFN-γ-like functional substance; and / or if it is a cat, the IFN-γ and / or IFN-γ-like functional substance is a feline IFN-γ and / or IFN-γ-like functional substance;

[0355] Preferably, the IFN-γ and / or IFN-γ-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is not an IFN-γ and / or IFN-γ-like functional substance endogenous to the subject. In other words, preferably, the IFN-γ and / or IFN-γ-like functional substance is not an IFN-γ and / or IFN-γ-like functional substance isolated from the subject's body, i.e., from the individual subject to be treated or prevented.

[0356] Preferably, the IFN-γ and / or IFN-γ-like functional substance for use according to the present invention and / or the IFN-γ and / or IFN-γ-like functional substance in steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may be, and preferably is, a recombinant IFN-γ and / or IFN-γ-like functional substance produced by any recombinant expression technique known to those skilled in the art, a chemically synthesized IFN-γ and / or IFN-γ-like functional substance synthesized by any production technique known to those skilled in the art, an artificially produced IFN-γ and / or IFN-γ-like functional substance produced by any production technique known to those skilled in the art, a naturally occurring IFN-γ and / or IFN-γ-like functional substance obtained from a natural source such as an animal or human, or any combination thereof. More preferably, the IFN-γ and / or IFN-γ-like functional substance is a recombinant IFN-γ and / or IFN-γ-like functional substance, a chemically synthesized IFN-γ and / or IFN-γ-like functional substance, an artificially produced IFN-γ and / or IFN-γ-like functional substance, or any combination thereof, even more preferably a recombinant IFN-γ and / or IFN-γ-like functional substance, and even more preferably a recombinant human IFN-γ1b protein (IFN-γ gamma 1b) preferably produced in genetically modified Escherichia coli (manufactured by Boehringer Ingelheim RCV GmbH & Co KG and commercially available in Germany from Boehringer Ingelheim Pharma GmbH & Co. KG under the trademark Imukin®, PZN: 06958744, Lot: M000487).

[0357] Furthermore, the IFN-γ and / or IFN-γ-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit may be derivatized, stabilized, fused to other proteins or peptides, conjugated with a polymer, contain amino acid analogs or artificial amino acids, covalently or non-covalently modified, e.g., by post-translational modification, e.g., glycosylated or methylated, and / or oligomerized, e.g., dimerized or trimerized, or not, so long as it is capable of and / or acts on PBMCs. More preferably, the modification pattern and / or oligomerization state is similar or identical to a peptide, protein or a fragment of any of these that occurs naturally in a vertebrate, preferably a mammal, more preferably a human or a mammal as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0358] Preferably, in any of the embodiments described herein, IFN-γ and / or IFN-γ-like functional substances are administered in a sufficiently low amount to avoid a systemic increase in the concentration of IFN-γ and / or IFN-γ-like functional substances in the subject's body. This avoids the generation of increased concentrations of IFN-γ and / or IFN-γ-like functional substances at the site of inflammation, such as an inflamed joint. As already mentioned above, for example, naive T cells can mature into cytotoxic cells that can function as pro-inflammatory cells in the presence of antigens / autoantigens / allergens. This reduces, cancels, or even reverses the beneficial effects achieved by the present invention, particularly the anti-inflammatory effects of the regulatory T cells and / or helper T cells, or subsets thereof, that may be generated.

[0359] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ and / or IFN-γ-like functional substance is administered in an amount that does not cause a systemic increase, more preferably an effective systemic increase, in the concentration of IFN-γ and / or IFN-γ-like functional substance in the subject, preferably the subject's blood, and / or that causes a systemic increase in the concentration of IFN-γ and / or IFN-γ-like functional substance. Preferably, the IFN-γ and / or IFN-γ-like functional substance is administered in an amount that is sufficiently low so that the systemic increase is ineffective.

[0360] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ and / or IFN-γ-like functional substance is administered in an amount that causes a local increase, preferably an effective local increase, in the concentration of the IFN-γ and / or IFN-γ-like functional substance in the subject, preferably in the skin tissue of the subject. Skin tissue is preferred because, unlike administration into the blood, there is no or less washout and dilution of the IFN-γ and / or IFN-γ-like functional substance.

[0361] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the production of an increased concentration, preferably an effective increased concentration, of the administered IFN-γ and / or IFN-γ-like functional substance is only local and not systemic in the subject.

[0362] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ and / or IFN-γ-like functional substance is administered in an amount that does not cause systemic activation, preferably effective systemic activation, of the individual receptors for the IFN-γ and / or IFN-γ-like functional substance, and / or does not cause systemic production, preferably effective systemic production, of the IFN-γ and / or IFN-γ-like functional substance, preferably in the subject.

[0363] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ and / or IFN-γ-like functional substance is administered in an amount that causes local activation, preferably effective local activation, of the respective receptors for the IFN-γ and / or IFN-γ-like functional substance, and / or causes local production, preferably effective local production, of IFN-γ and / or IFN-γ-like functional substance, preferably in the subject. Preferably, the activation and / or production, more preferably effective production and / or effective activation, is only local and not systemic in the subject.

[0364] Generally, 1 ng (nanogram) of IFN-γ corresponds to about 20 IU (international units) or less of IFN-γ. Some of the IFN-γ may be denatured or otherwise defective in that the mass remains constant but the biological activity of the IFN-γ is lost.

[0365] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ-like functional substance, preferably IFN-γ, is administered in an effective amount, preferably an effective total amount.

[0366] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ-like functional IFN-γ substance is administered to the skin of a subject in an amount, preferably a total amount, equivalent to 600 IU IFN-Γ / kg (International Units per kilogram) or less of the subject's body weight ("kg body weight" in this sense is IFN-γ equivalent to "kg body weight"). More preferably, the IFN-γ is administered in an amount, preferably a total amount, equivalent to 300 IU IFN-Γ / kg or less, even more preferably 200 IU IFN-Γ / kg or less, also more preferably 100 IU IFN-Γ / kg or less, even more preferably 50 IU IFN-Γ / kg or less, even more preferably 30 IU IFN-Γ / kg or less, even more preferably 20 IU IFN-Γ / kg or less, and even more preferably 6 IU IFN-Γ / kg or less. There is no lower limit to the amount per kg body weight as long as the beneficial effects of IFN-γ can be achieved, however, typically the lower limit is an amount equivalent to 0.04 IU IFN-Γ / kg or more, more preferably 0.2 IU IFN-Γ / kg or more, even more preferably 0.5 IU IFN-Γ / kg or more, also more preferably 1 IU IFN-Γ / kg or more, and even more preferably 1.5 IU IFN-Γ / kg or more. More preferably, the IFN-γ-like functional IFN-γ substance has an IFN-γ range corresponding to ≧0.04 IU IFN-Γ / kg and ≦600 IU IFN-Γ / kg, even more preferably ≧0.2 IU IFN-Γ / kg and ≦300 IU IFN-Γ / kg, also more preferably ≧0.5 IU IFN-Γ / kg and ≦200 IU IFN-Γ / kg, even more preferably ≧0.5 IU IFN-Γ / kg and ≦100 IU IFN-Γ / kg, even more preferably ≧0.5 IU IFN-Γ / kg and ≦50 IU IFN-Γ / kg, even more preferably ≧1 IU IFN-Γ / kg and ≦30 IU IFN-Γ / kg, and even more preferably ≧1.5 IU IFN-Γ / kg and ≦20 IU IFN-Γ / kg. IFN-γe), preferably in total.

[0367] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ-like functional IFN-γ agent is administered to the skin of the subject in an amount, preferably a total amount, corresponding to an activity of 30 ng IFN-γ / kg or less of the subject's body weight, preferably per administered dose. More preferably, the IFN-γ-like functional (aktinv) agent is administered in an amount, preferably a total amount, corresponding to an activity of 15 ng IFN-γ / kg or less, even more preferably 10 ng IFN-γ / kg or less, also more preferably 5 ng IFN-γ / kg or less, even more preferably 2.5 ng IFN-γ / kg or less, even more preferably 1.5 ng IFN-γ / kg or less, even more preferably 1 ng IFN-γ / kg or less, and even more preferably 0.3 ng IFN-γ / kg or less. There is no lower limit to the amount per kg body weight as long as the beneficial effects of IFN-γ can be achieved, however, typically the lower limit is an amount corresponding to an activity of 0.002 ng IFN-γ / kg or more, more preferably 0.025 ng IFN-γ / kg or more, even more preferably 0.01 ng IFN-γ / kg or more, also more preferably 0.02 mg / kg or more, even more preferably 0.05 ng IFN-γ / kg or more, and even more preferably 0.075 ng IFN-γ / kg or more.More preferably, the IFN-γ-like functional IFN-γ substance has a densitometric value of 30 ng IFN-γ / kg or less and 0.002 ng IFN-γ / kg or more, even more preferably 15 ng IFN-γ / kg or less and 0.025 ng IFN-γ / kg or more, also more preferably 10 ng IFN-γ / kg or less and 0.01 ng IFN-γ / kg or more, also more preferably 5 ng IFN-γ / kg or less and 0.01 ng IFN-γ / kg or more, even more preferably 2.5 ng IFN-γ / kg or less and 0.02 ng IFN-γ / kg or more, even more preferably 1.5 ng IFN-γ / kg or less and 0.02 ng IFN-γ / kg or more, even more preferably 1 ng IFN-γ / kg or less and 0.05 ng IFN-γ / kg or more, and even more preferably 0.3 ng IFN-γ / kg or less and 0.075 ng It is administered in an amount within the range of IFN-γ corresponding to an activity of IFN-γ / kg or more, preferably in total amount.

[0368] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ-like functional IFN-γ substance is administered in an amount, preferably a total amount, corresponding to 30,000 IU IFN-Γ or less, more preferably 15,000 IU IFN-Γ or less, even more preferably 10,000 IU IFN-Γ or less, also more preferably 5,000 IU IFN-Γ or less, and even more preferably 2,500 IU IFN-Γ or less, even more preferably 1,500 IU IFN-Γ or less, and even more preferably 1,000 IU IFN-Γ or less, and even more preferably 300 IU IFN-Γ or less, preferably per administered dose. There is no lower limit to the amount as long as the beneficial effects of IFN-γ can be achieved, however, typically the lower limit is an amount equivalent to 2 IU IFN-Γ or more, more preferably 10 IU IFN-Γ or more, even more preferably 20 IU IFN-Γ or more, also more preferably 30 IU IFN-Γ or more and still more preferably 50 IU IFN-Γ or more. More preferably, the IFN-γ-like functional IFN-γ substance preferably contains, per administered dose, 30,000 IU or less and 2 IU or more, even more preferably 15,000 IU or less and 2 IU or more, and more preferably 10,000 IU or less and 10 IU or more, and even more preferably 5,000 IU or less and 10 IU or more, and even more preferably 2,500 IU or less and 20 IU or more, and even more preferably 1,500 IU or less and 30 IU or more, and even more preferably 1,000 IU or less and 50 IU or more, and even more preferably 300 IU or less. It is administered in an amount, preferably a total amount, within the range of IFN-γ equivalent to less than IFN-Γ and more than 50 IU IFN-Γ.

[0369] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), the IFN-γ-like functional IFN-γ substance is administered in an amount, preferably a total amount, corresponding in activity to 1,500 ng IFN-γ or less, more preferably 750 ng IFN-γ or less, even more preferably 500 ng IFN-γ or less, also more preferably 250 ng IFN-γ or less, and even more preferably 125 ng IFN-γ or less, even more preferably 75 ng IFN-γ or less, and even more preferably 50 ng IFN-γ or less, and even more preferably 15 ng IFN-γ or less per administered dose. There is no lower limit to the amount, preferably the total amount, as long as the beneficial effects of IFN-γ can be achieved, however, typically the lower limit is an amount corresponding to an activity of 0.1 ng IFN-γ or more, more preferably 0.5 ng IFN-γ or more, even more preferably 1 ng IFN-γ or more and still more preferably 2 ng IFN-γ or more. More preferably, the IFN-γ-like functional IFN-γ substance is administered in an amount, preferably a total amount, within the range of IFN-γ corresponding to an activity of less than 1,500 ng IFN-γ and more than 0.1 ng IFN-γ, even more preferably less than 750 ng IFN-γ and more than 0.1 ng IFN-γ, also more preferably less than 500 ng IFN-γ and more than 0.1 ng IFN-γ, even more preferably less than 250 ng IFN-γ and more than 0.5 ng IFN-γ, even more preferably less than 125 ng IFN-γ and more than 0.5 ng IFN-γ, even more preferably less than 75 ng IFN-γ and more than 1 ng IFN-γ, even more preferably less than 50 ng IFN-γ and more than 1 ng IFN-γ, and even more preferably less than 15 ng IFN-γ and more than 2 ng IFN-γ per administered dose.

[0370] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1), and / or (C), IFN-γ is administered to the skin of a subject in an amount, preferably a total amount, of 600 IU / kg (International Units per kilogram) or less of subject body weight ("kg body weight" is, in this sense, equivalent to "kg body weight") per administered dose. More preferably, IFN-γ is administered in an amount, preferably a total amount, of 300 IU / kg or less, even more preferably 200 IU / kg or less, also more preferably 100 IU / kg or less, even more preferably 50 IU / kg or less, even more preferably 30 IU / kg or less, even more preferably 20 IU / kg or less, and even more preferably 6 IU / kg or less. As long as a beneficial effect can be achieved, there is no lower limit for the amount per kg body weight, however, the lower limit is usually 0.04 IU / kg or more, more preferably 0.2 IU / kg or more, even more preferably 0.5 IU / kg or more, more preferably 1 IU / kg or more, and even more preferably 1.5 IU / kg or more. More preferably, IFN-γ is administered in an amount, preferably a total amount, within the range of 0.04 IU / kg or more and 600 IU / kg or less, even more preferably 0.2 IU / kg or more and 300 IU / kg or more, more preferably 0.5 IU / kg or more and 200 IU / kg or less, even more preferably 0.5 IU / kg or more and 100 IU / kg or less, even more preferably 0.5 IU / kg or more and 50 IU / kg or less, even more preferably 1 IU / kg or more and 30 IU / kg or less, and even more preferably 1.5 IU / kg or more and 20 IU / kg or less.

[0371] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1), and / or (C), IFN-γ is administered to the skin of a subject in an amount, preferably a total amount, of 30 ng / kg or less of subject body weight per administered dose. More preferably, IFN-γ is administered in an amount, preferably a total amount, of 15 ng / kg or less, even more preferably 10 ng / kg or less, also more preferably 5 ng / kg or less, also more preferably 2.5 ng / kg or less, even more preferably 1.5 ng / kg or less, even more preferably 1 ng / kg or less, and even more preferably 0.3 ng / kg or less. As long as a beneficial effect can be achieved, there is no lower limit for the amount per kg body weight; however, the lower limit is usually 0.002 ng / kg or more, more preferably 0.025 ng / kg or more, even more preferably 0.01 ng / kg or more, also more preferably 0.02 mg / kg or more, even more preferably 0.05 ng / kg or more, and even more preferably 0.075 ng / kg or more. More preferably, IFN-γ is administered in an amount, preferably a total amount, within the range of 30 ng / kg or less and 0.002 ng / kg or more, even more preferably 15 ng / kg or less and 0.025 ng / kg or more, also more preferably 10 ng / kg or less and 0.01 ng / kg or more, also more preferably 5 ng / kg or less and 0.01 ng / kg or more, even more preferably 2.5 ng / kg or less and 0.02 ng / kg or more, even more preferably 1.5 ng / kg or less and 0.02 ng / kg or more, even more preferably 1 ng / kg or less and 0.05 ng / kg or more, and even more preferably 0.3 ng / kg or less and 0.075 ng / kg or more.

[0372] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1), and / or (C), IFN-γ is administered in an amount, preferably a total amount, of 30,000 IU or less, more preferably 15,000 IU or less, even more preferably 10,000 IU or less, also more preferably 5,000 IU or less, even more preferably 2,500 IU or less, even more preferably 1,500 IU or less, even more preferably 1,000 IU or less, and even more preferably 300 IU or less per administered dose. As long as a beneficial effect can be achieved, there is no lower limit on the amount; however, the lower limit is usually 2 IU or more, more preferably 10 IU or more, even more preferably 20 IU or more, also more preferably 30 IU or more, and also even more preferably 50 IU or more. More preferably, IFN-γ is administered in an amount, preferably a total amount, within the range of 30,000 IU or less and 2 IU or more, even more preferably 15,000 IU or less and 2 IU or more, also more preferably 10,000 IU or less and 10 IU or more, also more preferably 5,000 IU or less and 10 IU or more, even more preferably 2,500 IU or less and 20 IU or more, even more preferably 1,500 IU or less and 30 IU or more, even more preferably 1,000 IU or less and 50 IU or more, and even more preferably 300 IU or less and 50 IU or more, preferably per administered dose.

[0373] Preferably, in any of the embodiments described herein, particularly in steps (B), (B1) and / or (C), IFN-γ, preferably IFN-γ, is administered in an amount, preferably a total amount, of 1,500 ng or less, more preferably 750 ng or less, even more preferably 500 ng or less, also more preferably 250 ng or less, also more preferably 125 ng or less, even more preferably 75 ng or less, also more preferably 50 ng or less, and even more preferably 15 ng or less per administered dose. There is no lower limit on the amount, preferably the total amount, as long as a beneficial effect can be achieved; however, the lower limit is usually 0.1 ng or more, more preferably 0.5 ng or more, even more preferably 1 ng or more, and also even more preferably 2 ng or more. More preferably, IFN-γ is administered in an amount, preferably a total amount, within the range of 1,500 ng or less and 0.1 ng or more, even more preferably 750 ng or less and 0.1 ng or more, also more preferably 500 ng or less and 0.1 ng or more, also more preferably 250 ng or less and 0.5 ng or more, even more preferably 125 ng or less and 0.5 ng or more, still more preferably 75 ng or less and 1 ng or more, also more preferably 50 ng or less and 1 ng or more, and even more preferably 15 ng or less and 2 ng or more, per administered dose.

[0374] IFN-γ-like functional substances, such as IFN-γ, are capable of achieving the desired effects of PBMCs, in particular maturation, differentiation, proliferation, and / or transformation. In particular, PBMCs, particularly naive T cells, can mature in the presence of IFN-γ, and potential dendritic cells, such as Langerhans cells, can preferably mature into anti-inflammatory regulatory T cells in the absence of concurrent immune challenge and / or immune activity. As mentioned above, Langerhans cells are naturally present in the skin.

[0375] Furthermore, as already mentioned above, in order to accumulate in the skin tissue, PBMCs must pass from the capillary lumen through the capillary wall into the surrounding skin tissue (apart from step (A-8), here, PBMCs can be administered to the skin, for example, by injection). This migration process is known to occur naturally without any further action or effect, but without wishing to be bound by theory, IFN-γ-like functional substances, and in particular IFN-γ, may, but do not necessarily, provide a microenvironment that locally promotes such a migration process, thereby functioning as an attractant. Nevertheless, this does not replace the fact that PBMCs must accumulate in the skin capillaries or the skin capillary lumen prior to passing through the capillary wall. This requires means other than administration of an immunomodulatory substance and can be achieved by step (A) and, for example, any of the following steps (A-1) to (A-7). As already mentioned above, skin capillaries, in their non-dilated basal state, are too narrow for the bulky PBMCs to be forced into and through them, and the immunomodulatory substances administered in the present invention do not appear to provide for the presence of PBMCs within the skin capillaries.

[0376] As can be seen from the examples, IFN-γ has the effects of, among other things, reducing CRP levels, reducing joint swelling, reducing joint pressure sensitivity, reducing pain, reducing fatigue, and improving quality of life. CRP levels indicate the level of inflammation. Higher CRP levels indicate stronger inflammation, and a CRP of 1 or less is considered healthy. The reduction in CRP levels imparted by IFN-γ can be below 5 mg / L (milligrams per liter) or even below 1 mg / L. Furthermore, IFN-γ reduces the BASDAI and HAQ scores by several points. A high score indicates a relatively worse condition of the subject, and a lower score indicates an improved condition.

[0377] The expression "IL-2-like functional substance" or "IL-2-like functional substances" as referred to in any of the embodiments described herein may be, and preferably is, any substance that exerts an effect similar to or identical to IL-2 in the body of a subject when administered thereto. IL-2-like functional substances can encompass precursors, prodrugs, and propeptides of such substances that are not normally active as such, i.e., do not have immunomodulatory activity, but are converted into an active IL-2-like functional substance upon use in accordance with the present invention. Thus, preferably, it is any substance, molecule, peptide, protein, protein analog, protein variant, derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, and / or any derivative, fragment, and / or pharmaceutically acceptable salt of any of these. Accordingly, an IL-2-like functional substance is: - activates or is capable of activating a separate IL-2 receptor on the cell, which may be, for example, a receptor on PBMCs; and / or - causing or causing or capable of causing or causing the production of IL-2 and / or IL-2-like functional substances It is possible.

[0378] More preferably, the IL-2-like functional substance activates or is capable of activating an individual IL-2 receptor. The activation or ability to activate an individual IL-2 receptor may be direct and / or indirect.

[0379] Preferably, the IL-2-like functional substance activates or is capable of activating individual IL-2 receptors in the skin of a subject. The IL-2-like functional substance can be any naturally occurring or artificial IL-2-like functional substance, so long as it has sufficient biological activity, i.e., effective cross-reactivity in a subject, and is particularly capable of activating individual IL-2 receptors. Preferably, the IL-2-like functional substance is known to those skilled in the art as of the filing date of the present application.

[0380] More preferably, the IL-2-like functional substance is any peptide, protein, protein analog, protein variant, or any derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug, and / or pharmaceutically acceptable salt thereof.

[0381] In a preferred embodiment, the IL-2-like functional substance may be, inter alia, IL-2 and / or its derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts thereof, as detailed below.

[0382] More preferably, the IL-2-like functional substance is IL-2 and / or a derivative, fragment, biopharmaceutical, inducer, precursor, prodrug, mutein, codrug and / or pharmaceutically acceptable salt thereof.

[0383] The expression "IL-2" should preferably be interpreted broadly when referred to in any of the embodiments described herein. Typically, IL-2 activates or is capable of activating individual IL-2 receptors on cells. The IL-2 receptors may be, for example, receptors on PBMCs. Preferably, the activation or ability to activate is within the skin of a subject, more preferably in a locally effective amount within the skin of a subject, and even more preferably not in a systemically effective amount within the body of a subject. Preferably, IL-2 may be any type of IL-2 known to those skilled in the art. Furthermore, the present invention encompasses the use or medical use of such precursors, prodrugs, and propeptides of IL-2 that are not normally active as such, i.e., do not have immunomodulatory activity, but are converted into active IL-2 upon use in accordance with the present invention. Thus, they can be used in the methods or medical uses described herein, or in the preparation of pharmaceutical compositions, injectable dosage forms, topical dosage forms, medical devices, and / or kits described herein.

[0384] Preferably, the IL-2 may be any peptide, protein, protein analogue, protein variant and / or any derivative or pharmaceutically acceptable salt of any of these.

[0385] The IL-2 does not necessarily have to be derived from or identical to the IL-2 of the same genus and / or species to which the subject belongs, but can be any naturally occurring or artificial IL-2, so long as it has sufficient biological activity, i.e., effective cross-reactivity in the subject, and in particular is capable of activating individual IL-2 receptors. Preferably, the biological activity of the IL-2 and / or IL-2-like functional substance is sufficient to achieve treatment and / or prevention of an inflammatory disease, immunological disease, and / or autoimmune disease, preferably in the subject.

[0386] IL-2 and / or IL-2-like functional substances typically act on cells by binding to and activating individual IL-2 receptors on the cells. Activation of the individual receptors therefore typically results in the cellular effects as described above for immunomodulatory substances. Therefore, any embodiment referred to herein for immunomodulatory substances in relation to their effects on cells such as PBMCs is independently applicable mutatis mutandis to IL-2 and IL-2-like functional substances.

[0387] The activation or ability to activate individual IL-2 receptors by IL-2 and / or IL-2-like functional substances can be direct and / or indirect.

[0388] Unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances set forth above are applicable mutatis mutandis to IL-2 and / or IL-2-like functional substances, respectively. In particular, unless otherwise stated, the descriptions and definitions of cytokines or cytokine-like functional substances that "directly" and "indirectly" activate or are capable of activating individual IL-2 receptors are applicable mutatis mutandis to IL-2 and / or IL-2-like functional substances, respectively.

[0389] Preferably, the IL-2 and / or IL-2-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is capable of and / or acts on PBMCs by attracting, proliferating, differentiating and / or maturing, even more preferably by proliferating, differentiating and / or maturing, even more preferably by differentiating and / or maturing. Thus, more preferably, the IL-2 and / or IL-2-like functional substance is capable of and / or causes PBMCs to attract, proliferate, differentiate and / or mature. Even more preferably, the IL-2 and / or IL-2-like functional substance is capable of and / or causes PBMCs to proliferate, differentiate and / or mature. Even more preferably, the IL-2 and / or IL-2-like functional substance is capable of differentiating and / or maturing PBMCs and / or differentiates and / or matures PBMCs. Preferably, the PBMCs are naive PBMCs, more preferably lymphocytes, even more preferably T cells and / or B cells, also more preferably naive lymphocytes, even more preferably naive B cells and / or naive T cells, and even more preferably naive T cells.

[0390] More preferably, the IL-2 and / or IL-2-like functional substance is capable of and / or does act directly and / or indirectly on PBMCs.

[0391] More preferably, the IL-2 and / or IL-2-like functional substance is capable of and / or acts directly and / or indirectly on PBMCs within the subject, more preferably within the skin of the subject, as defined in any of the embodiments according to the present invention.

[0392] Even more preferably, the IL-2 and / or IL-2-like functional substance is capable of and / or directly causes the proliferation, differentiation and / or maturation of naive T cells in a subject, more preferably in the skin of a subject, as defined in any of the embodiments according to the present invention.

[0393] Unless otherwise stated, the descriptions and definitions of immunomodulatory substances set forth above are applicable mutatis mutandis to IL-2 and / or IL-2-like functional substances, independently. In particular, unless otherwise stated, the descriptions and definitions of immunomodulatory substances that act or are capable of acting "directly" and "indirectly" on PBMCs are applicable mutatis mutandis to IL-2 and / or IL-2-like functional substances, independently.

[0394] Preferably, the IL-2 and / or IL-2-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is similar or identical, preferably identical, to any IL-2 and / or IL-2-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body, more preferably a subject as defined in any of the embodiments according to the present invention. More preferably, the IL-2 and / or IL-2-like functional substance is similar or identical, preferably identical, to any peptide, protein or fragment of any of these of IL-2 and / or IL-2-like functional substance naturally occurring in a vertebrate, preferably a human or mammalian body as defined above, more preferably a subject as defined in any of the embodiments according to the present invention.

[0395] More preferably, the IL-2 and / or IL-2-like functional substance has 70% or more, even more preferably 85% or more, even more preferably 90% or more, even more preferably 95% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more and 100% or less amino acid sequence identity to any peptide, protein, or fragment of any of these of IL-2 and / or IL-2-like functional substance naturally occurring in a vertebrate, preferably a mammal, more preferably a human or mammal as defined above, more preferably a subject as defined in any of the embodiments according to the present invention. Preferably, the amino acid sequence identity includes substitutions, insertions, and / or deletions of amino acid residues relative to the naturally occurring peptide, protein, or fragment of any of these. Preferably, the amino acid sequence identity refers to the amino acid sequence of SEQ ID NO: 2, and more preferably, the subject is a human.

[0396] Preferably, the total number of substitutions, insertions and / or deletions of amino acid residues or the total number of substitutions, insertions and / or deletions combined is preferably 60 or less, more preferably 40 or less, even more preferably 20 or less, still more preferably 12 or less, still more preferably 8 or less, even more preferably 4 or less, still more preferably 2 or less and zero or more, and still more preferably zero, with reference to the amino acid sequence of SEQ ID NO: 2; in this case, more preferably, the subject is a human.

[0397] Even more preferably, the IL-2 and / or IL-2-like functional substance is identical to, or refers to amino acid sequence identity with, an endogenous immunomodulatory substance of the same genus and / or species to which the subject belongs. The expression "identical" typically means in this particular context that the IL-2 and / or IL-2-like functional substance is identical to, the IL-2 and / or IL-2-like functional substance of the same genus and / or species to which the subject belongs, with respect to its primary, secondary, tertiary and quaternary protein structure, and more preferably also taking into account modification patterns, in particular glycosylation.

[0398] Preferably, the IL-2 and / or IL-2-like functional substance for use according to the present invention and / or steps (B), (B1) and / or (C) of the method, pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit is derived from an individual belonging to the same genus and / or species as the subject, or is identical to the IL-2 and / or IL-2-like functional substance of the same genus and / or species to which the subject belongs. For example, if the subject is a human, the IL-2 and / or IL-2-like functional substance is human IL-2 and / or IL-2-like functional substance, more preferably a human IL-2 and / or IL-2-like functional substance that preferably comprises, and even more preferably consists of, the amino acid sequence of SEQ ID NO: 2 as an effective amino acid sequence; if the subject is a bovine, the IL-2 and / or IL-2-like functional substance is bovine IL-2 and / or IL-2-like functional substance; if the subject is a horse, the IL-2 and / or IL-2-like functional substance is equine IL-2 and / or IL-2-like functional substance; if the subject is a donkey, the IL-2 and / or IL-2-like functional substance is donkey IL-2 and / or IL-2-like functional substance; if the subject is an elephant, the IL-2 and / or IL-2-like functional substance is elephant IL-2 and / or is an IL-2-like functional substance; when it is a sheep, the IL-2 and / or IL-2-like functional substance is an ovine IL-2 and / or IL-2-like functional substance; when it is a goat, the IL-2 and / or IL-2-like functional substance is a caprine IL-2 and / or IL-2-like functional substance; when it is a pig, the IL-2 and / or IL-2-like functional substance is a porcine IL-2 and / or IL-2-like functional substance; when it is a rabbit, the IL-2 and / or IL-2-like functional substance is a rabbit IL-2 and / or IL-2-like functional substance; when it is a mouse, the IL-2 and / or IL-2-like functional substance is a mouse IL-2 and / or IL-2-like functional substance; when it is a rat, the IL-2 and / or IL-2-like functional substance is a rat IL-2 and / or IL-2-like functional substance;When the subject is a camel, the IL-2 and / or IL-2-like functional substance is a camel IL...

Claims

1. 1. An immunomodulatory and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, comprising: The method includes step (A), which comprises: (A-4) causing an increase in temperature on the skin of the subject; (A-0) A step of causing accumulation of PBMCs (peripheral blood mononuclear cells) in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) increasing the blood volume in the skin of the subject; (A-3) sO in the skin of the subject 2 causing an increase in oxygen saturation of hemoglobin and / or an increase in rHb (relative hemoglobin) in the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the skin of the subject; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method comprises the steps of: (B) administering an immunomodulatory agent to the skin of the subject; and / or (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). The immunomodulatory substance and / or skin conditioning agent further comprising:

2. In step (A-1) of the method, - Vasodilation increases sO 2 and / or determined based on rHb; and / or In step (A-2) of the method, - Blood volume expansion is determined based on sO2 and / or rHb in the skin; and / or In step (A-3) of the method, - sO2 increase of 2% or more and / or sO2 increase of 2 percentage points or more; and / or rHb increase of 2% or more and / or rHb increase of 2 AU (arbitrary units), In step (A-4) of the method, - temperature increase of 1% or more and / or temperature increase of 0.2°C or more, In step (A-6) of the method, conditioning energy is applied to produce: - dilation of capillaries in the skin of the subject, where the dilation is determined based on sO2 and / or rHb; and / or - an increase in blood volume within the subject's skin, where vasodilation is determined based on sO2 and / or rHb; and / or - an increase in sO2 and / or an increase in rHb in the skin of the subject, preferably an increase in sO2 of 2% or more and / or an increase in sO2 of 2% or more and / or an increase in rHb of 2% or more and / or an increase in rHb of 2% or more and / or an increase in rHb of 2% or more and / or an increase in rHb of 2 AU (arbitrary units) or more; and / or - an increase in temperature on the skin of the subject, preferably the temperature increases by 1% or more and / or by 0.2°C or more; and / or - redness on the subject's skin, Preferably, the conditioning energy is applied by using an energy application means; and / or In step (A-7) of the method, a skin conditioning agent is administered to produce: - dilation of capillaries in the skin of the subject, where the dilation is determined based on sO2 and / or rHb; and / or - an increase in blood volume within the subject's skin, where vasodilation is determined based on sO2 and / or rHb; and / or - an increase in sO2 and / or an increase in rHb in the skin of the subject, preferably an increase in sO2 of 2% or more and / or an increase in sO2 of 2% or more and / or an increase in rHb of 2% or more and / or an increase in rHb of 2% or more and / or an increase in rHb of 2% or more and / or an increase in rHb of 2 AU (arbitrary units) or more; and / or - an increase in temperature on the skin of the subject, preferably the temperature increases by 1% or more and / or by 0.2°C or more; and / or - redness on the subject's skin; and / or In step (A-8) of the method, PBMCs are injected into a local subcutaneous layer of skin.

10. An immunomodulatory substance and / or skin conditioning agent for use according to claim 1.

3. 2. The immunomodulatory substance and / or skin conditioning agent for use according to claim 1, wherein the immunomodulatory substance for use and the immunomodulatory substance in step (B) and / or step (C) are cytokine-like functional substances, preferably interferon-like functional substances, interleukin-like functional substances and / or neurotrophic factor-like functional substances, more preferably IFN-γ-like functional substances, IL-4-like functional substances, BDNF-like functional substances and / or IL-2-like functional substances, even more preferably IFN-γ (interferon-gamma), IL-4 (interleukin 4), BDNF (brain-derived neurotrophic factor) and / or IL-2 (interleukin 2), and / or any derivatives, fragments, biopharmaceuticals, inducers, precursors, prodrugs, muteins, codrugs and / or pharmaceutically acceptable salts of any of these, and more preferably IFN-γ, IL-4, BDNF and / or IL-2.

4. - IFN-γ is administered in an amount of 600 IU / kg of the subject's body weight or less; in an amount of 30 ng / kg of the subject's body weight or less; in a total amount of 30,000 IU or less; and / or in a total amount of 1,500 ng or less; - IL-4 is administered in an amount of 20 ng / kg or less of the subject's body weight; and / or in a total amount of 1,000 ng or less; - BDNF is administered in an amount of 10 ng / kg of subject body weight or less; and / or in a total amount of 500 ng or less; and / or - IL-2 is administered in an amount of 10 IU / kg of subject body weight or less; in an amount of 0.6 ng / kg of subject body weight or less; in a total amount of 500 IU or less; and / or in a total amount of 30.5 ng or less; 4. An immunomodulatory substance and / or skin conditioning agent for use according to claim 3.

5. 2. An immunomodulatory substance and / or skin conditioning agent for use according to claim 1, wherein the inflammatory, immunological and / or autoimmune disease to be treated and / or prevented comprises, preferably consists of, arthritis, synovitis, tenosynovitis, inflammatory rheumatic diseases, Hashimoto's disease, Graves' disease, Crohn's disease and / or multiple sclerosis.

6. 1. An immunomodulatory substance and / or skin conditioning agent for use in a method for treating and / or preventing an inflammatory, immunological, and / or autoimmune disease in a subject, wherein the skin conditioning agent for use and the skin conditioning agent in step (A-7) of the method comprise a blood circulation increasing agent, a vasodilator, a skin temperature increasing agent, a skin sO 2 and / or skin rHb increasing agents, preferably skin conditioning agents, including nitrates, alpha blockers, ACE inhibitors, ginkgo preparations such as ginkgo balm, calcium channel blockers, vasodilators such as dihydralazine, minoxidil, dihydroergotoxine, nicotinic acid analogs, methylnicotinate, wormwood, capsaicine, pentoxifylline, vasodilator-containing creams, methylnicotinate-containing creams, Kytta® heating balm, and / or any combination thereof.

7. skin conditioning agents; and - Immunomodulatory substances A pharmaceutical composition (I) comprising:

8. - IFN-γ-like functional substances; - IL-4-like functional substances; - BDNF-like functional substances; and / or - IL-2-like functional substances A pharmaceutical composition (II) comprising: - in an amount equivalent to 600 IU IFN-γ / kg of subject body weight or less; at an amount corresponding to an activity of 30 ng IFN-γ / kg subject body weight or less; in a total amount equivalent to 30,000 IU IFN-γ or less; and / or The total amount of IFN-γ equivalent to 1,500 ng or less IFN-γ-like functional substances; in an amount corresponding to an activity of 20 ng IL-4 / kg body weight or less; and / or The total amount of activity equivalent to 1,000 ng IL-4 or less IL-4-like functional substances; in an amount corresponding to an activity of 10 ng BDNF / kg body weight or less; and / or The total amount of activity corresponds to less than 500ng BDNF. BDNF-like functional substances; and / or - in an amount equivalent to 10 IU / kg or less of subject body weight; at an amount of 0.6 ng / kg subject body weight or less; in a total amount corresponding to an activity of 500 IU IL-2 or less; and / or The total amount of activity corresponds to 30.5 ng IL-2 or less IL-2-like functional substance and Preferably, - IFN-γ; - IL-4; - BDNF; and / or - IL-2 Including, IFN-γ in an amount of 600 IU / kg of subject body weight or less; in an amount of 30 ng / kg of subject body weight or less; in a total amount of 30,000 IU or less; and / or in a total amount of 1,500 ng or less; IL-4 in an amount not exceeding 20 ng / kg of subject body weight; and / or in a total amount not exceeding 1,000 ng; BDNF in an amount equal to or less than 10 ng / kg of subject body weight; and / or in a total amount equal to or less than 500 ng; and / or IL-2 in an amount of 10 IU / kg of subject body weight or less; in an amount of 0.6 ng / kg of subject body weight or less; in a total amount of 500 IU or less; and / or in a total amount of 30.5 ng or less Suitable for delivering The above pharmaceutical composition (II).

9. - IFN-γ-like functional substances at a concentration corresponding to 100,000 IU IFN-γ / mL or IU IFN-γ / g or less, or at a concentration corresponding to an activity of 5,000 ng IFN-γ / mL or ng IFN-γ / g or less; - IL-4-like functional substances at a concentration corresponding to an activity of 1,000 ng IL-4 / mL or less than ng / g; - BDNF-like functional substances at a concentration corresponding to an activity of 1,500 ng BDNF / mL or less than ng / g; - IL-2-like functional substances at a concentration equivalent to 100,000 IU IL-2 / mL or IU IL-2 / g or less, or at a concentration corresponding to an activity of 6100 ng IL-2 / mL or ng IL-2 / g or less. Including, Preferably, IFN-γ at a concentration of less than or equal to 100,000 IU / mL or IU / g, or less than or equal to 5,000 ng / mL or ng / g; - IL-4 at a concentration of 1,000 ng / mL or less than ng / g; BDNF at a concentration of 1,500 ng / mL or less; and / or IL-2 at a concentration of less than or equal to 100,000 IU / mL or IU / g, or less than or equal to 6100 ng / mL or ng / g Including, Pharmaceutical composition (III).

10. - IFN-γ-like functional substances; - IL-4-like functional substances; - BDNF-like functional substances; or - IL-2-like functional substances, and immunomodulatory substances Pharmaceutical composition (IV) comprising: - if it comprises an IFN-γ-like functional substance, the immunomodulatory substance is different from the IFN-γ-like functional substance; - if it comprises an IL-4-like functional substance, the immunomodulatory substance is different from the IL-4-like functional substance; - if it comprises a BDNF-like functional substance, the immunomodulatory substance is different from the BDNF-like functional substance; and - if an IL-2-like functional substance is included, the immunomodulatory substance is different from the IL-2-like functional substance; The above pharmaceutical composition (IV).

11. - IFN-γ-like functional substances; - IL-4-like functional substances; - BDNF-like functional substances; or - IL-2-like functional substances, and immunomodulatory substances An injectable dosage form (I) comprising: - if it comprises an IFN-γ-like functional substance, the immunomodulatory substance is different from the IFN-γ-like functional substance; - if it comprises an IL-4-like functional substance, the immunomodulatory substance is different from the IL-4-like functional substance; - if it comprises a BDNF-like functional substance, the immunomodulatory substance is different from the BDNF-like functional substance; and - if an IL-2-like functional substance is included, the immunomodulatory substance is different from the IL-2-like functional substance; The above injectable dosage form (I).

12. - IFN-γ-like functional substances in a total amount corresponding to not more than 30,000 IU IFN-γ and / or in a total amount corresponding in activity to not more than 1,500 ng IFN-γ; - IL-4-like functional substances in a total amount corresponding to an activity of not more than 1,000 ng of IL-4; - BDNF-like functional substances in a total amount corresponding to an activity of 500 ng BDNF or less; or - IL-2-like functional substances in a total amount equivalent to 1,000 IU IL-2 or less and / or in a total amount equivalent to an activity of 61 ng IL-2 or less Including, Preferably, - IFN-γ in a total amount not exceeding 30,000 IU and / or in a total amount not exceeding 1,500 ng; - IL-4 in a total amount of 1,000 ng or less; - BDNF in a total amount of 500 ng or less; or IL-2 in a total dose of 1,000 IU or less and / or in a total dose of 61 ng or less Including, Injectable dosage form (II).

13. - IFN-γ-like functional substances; - IL-4-like functional substances; - BDNF-like functional substances; or - IL-2-like functional substances A topical dosage form (I) comprising:

14. - immunomodulatory substances; - Energizing components (II) A topical dosage form comprising:

15. - a skin conditioning part (110); and - Applicator part (120) A medical device (100) comprising: the skin conditioning portion (110) and the applicator portion (120) are configured to cooperatively interact to administer an amount of a first therapeutic agent to the subject's skin (102) using the applicator portion (120) along with an amount of conditioning treatment using the skin conditioning portion (110); and / or The skin conditioning portion (110) and the applicator portion (120) are configured to act on the skin (102) of the subject; The medical device (100) described above.

16. (i) an immunomodulatory agent; and (ii) a skin conditioning agent; and / or (iii) Energy imparting means A kit (I) comprising:

17. (i) an IFN-γ-like functional substance, an IL-4-like functional substance, a BDNF-like functional substance, and / or an IL-2-like functional substance; and (ii) immunomodulatory substances; Kit (II) comprising: - if it comprises an IFN-γ-like functional substance, the immunomodulatory substance is different from the IFN-γ-like functional substance; - if it comprises an IL-4-like functional substance, the immunomodulatory substance is different from the IL-4-like functional substance; - if it comprises a BDNF-like functional substance, the immunomodulatory substance is different from the BDNF-like functional substance; and - if an IL-2-like functional substance is included, the immunomodulatory substance is different from the IL-2-like functional substance; The above kit (II).

18. (i) the injectable dosage form of claim 11; and (ii) a skin conditioning agent; and / or (iii) Energy imparting means A kit (III) comprising:

19. (i) a topical dosage form according to claim 13; and (ii) a skin conditioning agent; and / or (iv) Energy imparting means A kit (IV) comprising:

20. - applicator part (120); and - a skin conditioning part (110); and - optionally a reservoir (121) containing a first therapeutic agent, such as an immunomodulatory agent, the reservoir (121) being configured for fluid coupling to the applicator portion (120); A kit (V) comprising:

21. For use as a medicine, preferably for use in the treatment and / or prevention of inflammatory, immunological and / or autoimmune diseases, A pharmaceutical composition (I) according to claim 7; Pharmaceutical composition (II) according to claim 8; The pharmaceutical composition (III) according to claim 9; Pharmaceutical composition (IV) according to claim 10; 12. The injectable dosage form (I) according to claim 11; 13. The injectable dosage form (II) according to claim 12; A topical dosage form (I) according to claim 13; A topical dosage form (II) according to claim 14; A kit (I) according to claim 16; Kit (II) according to claim 17; A kit (III) according to claim 18; and / or 20. The kit (IV) according to claim 19.

22. A pharmaceutical composition (I) according to claim 7, suitable for and / or for use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject; Pharmaceutical composition (II) according to claim 8; The pharmaceutical composition (III) according to claim 9; Pharmaceutical composition (IV) according to claim 10; 12. The injectable dosage form (I) according to claim 11; 13. The injectable dosage form (II) according to claim 12; A topical dosage form (I) according to claim 13; A topical dosage form (II) according to claim 14; A medical device (100) according to claim 15; A kit (I) according to claim 16; Kit (II) according to claim 17; 19. The kit (III) according to claim 18; Kit (IV) according to claim 19; and / or The kit (V) according to claim 20 And, The method includes step (A), which comprises: (A-4) causing an increase in temperature on the skin of the subject; (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) increasing the blood volume in the skin of the subject; (A-3) sO in the skin of the subject 2 causing an increase in rHb and / or an increase in rHb in the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the skin of the subject; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method comprises the steps of: (B) administering an immunomodulatory agent to the skin of the subject; and / or (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). The pharmaceutical composition, injectable dosage form, topical dosage form, medical device and / or kit as described above, further comprising:

23. For use in a method for treating and / or preventing an inflammatory, immunological and / or autoimmune disease in a subject, - skin conditioning agents; or - Immunomodulatory substances A pharmaceutical composition (X), a topical dosage form (X), an injectable dosage form (X) and / or a kit (X), comprising: The method includes step (A), which comprises: (A-4) causing an increase in temperature on the skin of the subject; (A-0) causing accumulation of PBMCs in the skin of a subject; (A-1) causing capillary dilation in the skin of a subject; (A-2) increasing the blood volume in the skin of the subject; (A-3) sO in the skin of the subject 2 causing an increase in rHb and / or an increase in rHb in the skin of the subject; (A-5) causing redness on the skin of the subject; (A-6) applying conditioning energy to the skin of the subject; (A-7) administering a skin conditioning agent to the skin of the subject; and / or (A-8) Administering PBMCs into the skin of the subject and the method comprises the steps of: (B) administering an immunomodulatory agent to the skin of the subject; and / or (C) administering an immunomodulatory agent to the skin of the subject. wherein the immunomodulatory agent administered in step (C) is different from the immunomodulatory agent administered in step (B). The pharmaceutical composition, topical dosage form, injectable dosage form and / or kit as described above, further comprising:

24. Use of a pharmaceutical composition according to any one of claims 7, 8, 9 and / or 10 for manufacturing an article, preferably an injectable dosage form according to claim 11 and / or 12, and / or a topical dosage form according to claim 13 and / or 14, or use of a pharmaceutical composition according to any one of claims 7, 8, 9 and / or 10 and / or an injectable dosage form according to claim 11 and / or 12 for manufacturing a medical device, preferably a medical device (100) according to claim 15.

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