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Cell Population Having Immunoregulatory Activity, Method for Isolation and Uses

a cell population and immunoregulatory technology, applied in the field of cell population having immunoregulatory activity, method for isolation and use, can solve the problems of affecting the survival of patients, causing death, and causing harm or deadly immunological responses, so as to prevent, treat or improve the

Inactive Publication Date: 2009-05-21
TIGENIX SAU +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0260]FIG. 21A shows the cells bright field image of the washed cell population. FIG. 21B shows the same population using fluorescence microscopy using Green Fluorescent Protein filters known in the art. The uptake of the fluorescent marker visible in FIG. 21B shows that the cells are able to phagocytose small weight molecules and this indicates that these cells are capable of antigen-presentation via HLA class II induced by additional treatment of the cells with IFN-γ.

Problems solved by technology

Although methods are available for treating these diseases, many current therapies provide less than adequate results.
Antibodies, T cells and macrophages provide beneficial protection, but can also produce harmful or deadly immunological responses.
The dilemma faced when administering immunosuppressive agents, however, is the more effectively the autoimmune disease is treated, the more defenseless the patient is left to attack from infections, and also the more susceptible for developing tumours.
These symptoms can greatly impact the patients' well being, quality of life, and capacity of function.
Therapeutic agents currently used for CD, including aminosalicylates, corticosteroids, azathioprine, 6-mercaptopurine, antibiotics, and methotrexate, are not entirely effective, nonspecific, and with multiple adverse side effects.
However, since it has a systemic effect, and TNF is a very pleiotropic factor, severe side effects are relatively common, and its long-term safety is still to be determined.
Also, the efficacy is also limited because many of the inflammatory processes that occur in the patients are not dependant on TNF signalling.
Inflammation results, and the cartilage and tissues in and around the joints are damaged or destroyed.
Anti-TNF humanized monoclonal antibodies, such as Infliximab are also used; however, it has many secondary effects or side effects and its efficacy is quite low.
Although these are well-established treatments for arthritis, very few patients remit on these lines of treatment alone, and difficult treatment issues still remain for patients with rheumatoid arthritis.
In general, the current treatments for chronic inflammatory disorders have a very limited efficiency, and many of them have a high incidence of side effects or cannot completely prevent disease progression.
So far, no treatment is ideal, and there is no cure for these type of pathologies.
However, the molecular mechanisms responsible for the immunosuppressive effects of said cells have not been unequivocally identified.

Method used

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  • Cell Population Having Immunoregulatory Activity, Method for Isolation and Uses
  • Cell Population Having Immunoregulatory Activity, Method for Isolation and Uses
  • Cell Population Having Immunoregulatory Activity, Method for Isolation and Uses

Examples

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example 1

Isolation and Expansion of Cells of the Invention

I. Material and Methods

[0187]Isolation of Cells of the Invention from Adipose Tissue

[0188]Human adipose tissue was obtained by liposuction, under local anaesthesia and general sedation. A hollow blunt-tipped cannula was introduced into the subcutaneous space through a small incision (less than 0.5 cm in diameter). With gentle suction, the cannula was moved through the adipose tissue abdominal-wall compartment for mechanical disruption of the fatty tissue. A saline solution and the vasoconstrictor epinephrine were injected into the adipose tissue compartment to minimize blood loss. In this way, 80 to 100 ml of raw lipoaspirate were obtained from each patient to be treated.

[0189]The raw lipoaspirate was washed extensively with sterile phosphate-buffered saline (PBS; Gibco BRL, Paisley, Scotland, UK) to remove blood cells, saline and local anaesthetic. The extracellular matrix was digested with a solution of type II collagenase (0.075%; ...

example 2

Induction of Indolamine 2,3-dioxygenase (IDO) by interferon-gamma (IFN-γ)

I. Material and Methods

[0212]The cells of the invention isolated from human adipose tissue (Example 1), were seeded onto tissue culture plates at a density of 10,000 cells / cm2, and incubated for 48 hours in the conditions previously described for cell expansion. Then, different pro-inflammatory stimuli were added to the culture medium, including:[0213]Interleukin-1 (IL-1): 3 ng / ml[0214]Interferon-gamma (IFN-γ): 3 ng / ml[0215]Tumor necrosis factor-alpha (TNF-α): 5 ng / ml[0216]Lipopolysaccharide (LPS): 100 ng / ml

[0217]The cells were incubated in the presence of the corresponding stimulus for periods ranging form 30 minutes to 48 hours, and then they were collected by trypsin digestion, and lysed in RIPA buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM PMSF (phenyl-methylsulphonylfluoride), 1 mM EDTA (ethylenediaminetetraacetic acid), 5 μg / ml Aprotinin, 5 μg / ml Leupeptin, 1% Triton x-100, 1% Sodium deoxycholate, 0.1%...

example 3

Tumorigenic Behaviour

I. Material and Methods

[0220]This experiment was performed with cells of the invention isolated from human adipose tissue as described in Example 1. The cell samples were cultivated for 2-7 weeks prior to the subcutaneous implantation in immunodeficient mice (5×106 cells / mouse). The mice were nu / nu strain obtained from Charles River Laboratories. Mice lacked thymus and were T-cell deficient. The implanted mice were followed-up for 4 months prior to sacrifice and pathological study.

[0221]Pathological study: A necropsy was performed on all animals. The animals were examined for gross abnormalities in the brain, lungs, heart, liver, kidneys, spleen, abdominal lymph nodes and injection site. Tissues were collected for a histological examination (parafin section and hematoxilin-eosin (H&E) staining), including injection site, lungs and lymph nodes.

[0222]The teratome cellular line (N-TERA) was used as a positive control, which was implanted under identical conditions....

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Abstract

The present invention provides a population of connective tissue derived cells that respond to interferon-gamma (IFN-γ) by expressing indolamine-2,3-dioxygenase (IDO) for use in preventing, treating or ameliorating one or more symptoms associated with disorders in which modulation of a subject's immune system is beneficial, including, but not limited to, autoimmune diseases, inflammatory disorders, and immunologically mediated diseases including rejection of transplanted organs and tissues.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the prevention, treatment or amelioration of one or more symptoms of disorders in which modulation of a subject's immune system is beneficial utilizing cell populations derived from adult tissues. In particular, the present invention provides a population of connective tissue derived cells that respond to interferon-gamma (IFN-γ) by expressing indolamine-2,3-dioxygenase (IDO) for use in preventing, treating or ameliorating one or more symptoms associated with disorders in which modulation of a subject's immune system is beneficial, including, but not limited to, autoimmune diseases, inflammatory disorders, and immunologically mediated diseases including rejection of transplanted organs and tissues.BACKGROUND OF THE INVENTION[0002]The immune system in higher vertebrates represents the first line of defense against various antigens that can enter the vertebrate body, including micro-organisms such as bacteria, fungi and viru...

Claims

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Application Information

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IPC IPC(8): A61K38/21C12N5/06C12N5/08A61P37/02C12Q1/02A61K35/12A61K39/00C12N5/0775C12N5/0783
CPCA61K2035/124A61K39/0008C12N5/0667C12N5/0636C12N2501/24A61K2039/5156A61K39/001A61K2035/122A61K35/28C12N5/0637A61K39/46433A61K39/4611A61K39/4621A61P1/00A61P1/04A61P19/02A61P29/00A61P37/02A61P37/06A61P37/08A61K35/35C12N5/0662
Inventor BUSCHER, DIRKGONZALEZ DE LA PENA, MANUEL ANGELMORA, MARIO DELGADO
Owner TIGENIX SAU
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