Type 1 helper T cell-increasing agents, foods, and medicines

Abstract

To provide a Th1 increasing agent that reduces the limits on storage conditions and feeding forms, and can increase Th1 sufficiently at a lower dose.SOLUTION: A Th1 increasing agent contains a cellulose derivative that has a degree of substitution of butyryl of 0.3 or more and 2.6 or less and a total degree of substitution of 0.5 or more and 2.8 or less, as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an agent for increasing type 1 helper T cells, a food product, and a medicine. [Background technology]

[0002] The immune system is a defense mechanism that protects the body from foreign substances such as pathogens, virus-infected cells, and cancer cells, and involves white blood cells such as lymphocytes and neutrophils. Lymphocytes include B cells, which are involved in humoral immunity, and T cells, which are involved in cellular immunity. T cells include CD4+ T cells and CD8+ T cells.

[0003] Most of the CD4 positive T cells are called helper T cells. Helper T cells are born in the thymus and released outside the thymus as naive T cells (immature T cells). Naive T cells activated by antigen stimulation differentiate into type 1 helper T cells (hereinafter sometimes referred to as Th1), type 2 helper T cells (Th2), or type 17 helper T cells (Th17) with specific functions depending on the extracellular environment such as cytokines present at the time of activation, and induce an optimal immune response to eliminate the antigen. In addition, most of the CD8 positive T cells differentiate into cytotoxic T cells (CTL) by antigen stimulation.

[0004] Interleukin (IL)-12 and interferon gamma (IFN-γ) are involved in promoting differentiation into Th1. IL-12 is produced by dendritic cells and macrophages, while IFN-γ is mainly produced by Th1 and natural killer (NK) cells.

[0005] Th1 then produces cytokines such as interferon-γ (IFN-γ) and interleukin (IL)-2, which activate cytotoxic T cells, which then destroy target cells.

[0006] As a treatment for cancer and the like that utilizes the immune system, in addition to immunotherapy that utilizes cytotoxic T cells, immunotherapy that utilizes Th1, which supports the activity of cytotoxic T cells, has attracted attention.

[0007] Patent Document 1 describes a Th1 inducer that contains as an active ingredient lactic acid bacteria cells capable of inducing IL-12 production, the cells being microparticulated to a particle size of less than 1 micron and prevented from reaggregating by a dispersant or excipient. It also describes that "Th1 induction" refers to promoting differentiation of Th0 cells (naive Th cells) into Th1 cells by efficiently producing IL-12 from antigen-presenting cells, thereby creating a Th1-dominant state in the body.

[0008] Patent Document 2 describes an oral cytokine inducer that is characterized by containing microbial cells carrying a cytokine-inducing substance on the surface. Patent Document 2 also states the following: "According to the present invention, oral administration can promote the in vivo production of cytokines such as IFN-γ and IL-8, which play important roles in immune responses, and can facilitate the treatment and prevention of many diseases, including infectious diseases, autoimmune diseases, inflammation, and tumors."

[0009] In Non-Patent Document 1, a survey was conducted on fermented milk and lactic acid bacteria beverages, and it was found that when bifidobacteria were included, the viable cell count was 2 × 10 6 ~3×10 8 cfu / g, and 2×10 for lactic acid bacteria. 7 ~1×10 9 It was reported that the cfu / g. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Patent No. 4621218 [Patent Document 2] JP 2003-063991 A [Non-patent literature]

[0011] [Non-Patent Document 1] Kenji Tayama et al., “Viable cell count and viability of bifidobacteria in fermented dairy products”, Journal of the Japanese Society for Food and Nutrition, 2013, Vol. 24, No. 2, p. 118-123 Summary of the Invention [Problem to be solved by the invention]

[0012] Patent Document 1 describes the use of lactic acid bacteria cells to produce IL-12 from mouse macrophage fluid, but does not demonstrate the effect of oral administration.

[0013] In addition, Patent Document 2 describes a method for injecting transformed lactic acid bacteria into mice at 5 × 10 8 It is described that the induction of IFN-γ in the blood was significantly observed when the CFU / mouse was intragastrically administered three times a week. As shown in Non-Patent Document 1, the viable cell count of bifidobacteria or lactic acid bacteria is at most 5 × 10 per gram of fermented milk or lactic acid bacteria beverage. 8 Since the amount is about cfu, when converted into the amount of fermented milk or lactic acid bacteria drink, about 3 g would need to be administered per week.

[0014] Although it depends on the species and age, considering that mice eat about 3g per day, it is necessary to feed them 14% or more by weight of fermented milk and lactobacillus beverage. This is an unrealistic amount for humans to consume, and is painful to take orally as a medicine, and if taken as food, it is an amount that will ruin the enjoyment of normal meals.

[0015] Furthermore, in such conventional methods using specific bacteria, there are many restrictions on storage conditions and feeding methods, such as the need to seal and refrigerate the bacteria and set a relatively short storage period of about a few weeks in order to keep the intended bacteria alive and suppress the growth of other bacteria, as occurs during the storage and transportation of fermented milk such as yogurt and lactic acid bacteria drinks.

[0016] An object of the present invention is to provide a Th1 enhancer that reduces restrictions on storage conditions and administration form and can sufficiently increase Th1 at a lower dose. [Means for solving the problem]

[0017] The first aspect of the present invention relates to an agent for increasing type 1 helper T cells (Th1), which comprises as an active ingredient a cellulose derivative having a butyryl substitution degree of 0.3 or more and 2.6 or less and a total substitution degree of 0.5 or more and 2.8 or less.

[0018] The agent for expanding type 1 helper T cells (Th1) may have a butyryl substitution degree of the cellulose derivative of 0.3 or more and 1.5 or less, and a total substitution degree of 0.5 or more and 1.5 or less.

[0019] The agent for expanding type 1 helper T cells (Th1) may have a degree of acetyl substitution of the cellulose derivative that is more than 0 and is 2.5 or less.

[0020] The agent for expanding type 1 helper T cells (Th1) may be such that the degree of acetyl substitution of the cellulose derivative is 0.

[0021] In the agent for expanding type 1 helper T cells (Th1), the cellulose derivative may be cellulose butyrate or cellulose acetate butyrate.

[0022] The second aspect of the present invention relates to a food product containing the agent for increasing type 1 helper T cells (Th1).

[0023] A third aspect of the present invention relates to a food product containing the agent for increasing type 1 helper T cells (Th1), wherein the cellulose derivative is contained in an amount of 1% by weight or more and 5% by weight or less.

[0024] The fourth aspect of the present invention relates to a medicine containing the agent for increasing type 1 helper T cells (Th1).

[0025] A fifth aspect of the present invention relates to a pharmaceutical agent for preventing and / or treating a tumor, which comprises the agent for increasing type 1 helper T cells (Th1). Effect of the Invention

[0026] According to the present invention, it is possible to provide a Th1 enhancer which reduces the restrictions on storage conditions and administration form and can sufficiently increase Th1 at a lower dose. [Brief description of the drawings]

[0027] [Figure 1] FIG. 13C-NMR spectrum of acetylated or butyrylated cellulose acetate butyrate. [Diagram 2] FIG. 13C-NMR spectrum of acetylated or butyrylated regenerated cellulose. [Diagram 3] FIG. 1 shows the 13C-NMR spectrum of acetylated cellulose butyrate. [Figure 4] FIG. 1 shows the results of flow cytometry for Th1. [Diagram 5] FIG. 1 shows flow cytometry-based quantitative assessment of Th1. [Figure 6] FIG. 1 shows the results of flow cytometry for INF-γ producing cells. [Figure 7] FIG. 1 shows flow cytometry-based quantitative assessment of INF-γ producing cells. [Figure 8] FIG. 1 shows quantitative PCR results. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] An example of a preferred embodiment will now be described in detail. The Th1 enhancer according to the present disclosure contains as an active ingredient a cellulose derivative having a butyryl substitution degree of 0.3 or more and 2.6 or less and a total substitution degree of 0.5 or more and 2.8 or less.

[0029] [Cellulose derivatives] The cellulose derivative of the present disclosure has a butyryl substitution degree of 0.3 or more and 2.6 or less, preferably 0.3 or more and 1.5 or less, more preferably 0.5 or more and 1.5 or less, even more preferably 0.7 or more and 1.4 or less, and most preferably 0.8 or more and 1.3 or less. If the butyryl substitution degree is less than 0.3, depending on the dosage, generally less butyric acid is liberated in the digestive tract, making it difficult to obtain the desired effect of increasing Th1. In addition, if the butyryl substitution degree is more than 2.6, decomposition by bacteria such as enterobacteria in the digestive tract is inhibited, probably because of too high hydrophobicity, and less butyric acid is liberated.

[0030] Next, the cellulose derivative of the present disclosure has a total degree of substitution of 0.5 or more and 2.8 or less, preferably 0.5 or more and 2.0 or less, more preferably 0.5 or more and 1.5 or less, and even more preferably 1.0 or more and 1.5 or less. If the total degree of substitution is less than 0.5, depending on the dosage, generally less butyric acid is liberated in the digestive tract, making it difficult to obtain the desired effect of increasing Th1. Also, if the total degree of substitution is more than 2.8, decomposition by bacteria such as enterobacteria in the digestive tract is inhibited, probably because of too high hydrophobicity, and less butyric acid is liberated.

[0031] Here, the butyryl substitution degree refers to the sum of the number of butyryl groups substituting the hydrogen atoms of the hydroxyl groups at the 2nd, 3rd, and 6th positions per repeating unit (glucopyranose unit) of cellulose. The same applies to the degree of substitution by other substituents such as the degree of acetyl substitution. The total substitution degree refers to the sum of the degree of butyryl substitution and the degree of substitution by other substituents.

[0032] From the viewpoint of butyric acid delivery to the digestive tract such as the large intestine, the substituent of the cellulose derivative of the present disclosure is preferably only a butyryl group, in other words, the cellulose derivative of the present disclosure has the same butyryl substitution degree and total substitution degree, but may be substituted with a substituent other than a butyryl group. Examples of the substituent other than a butyryl group include an acetyl group, a carboxyl group, a carboxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a methyl group. A part of the 6-position (hydroxymethyl group) of cellulose may be oxidized to a carboxyl group. From the viewpoint of promoting decomposition by bacteria such as enterobacteria in the digestive tract and increasing the amount of liberated butyric acid, it is preferable to impart hydrophilicity to the cellulose derivative, and from this viewpoint, among these substituents, the introduction of an acetyl group, a carboxymethyl group, or a carboxyl group, which is less hydrophobic than a butyryl group, is effective. The cellulose derivative may be substituted with one or more of the substituents other than a butyryl group.

[0033] In particular, the case where the cellulose derivative of the present disclosure is substituted with an acetyl group, which has a lower hydrophobicity than the butyryl group, as a substituent other than the butyryl group will be described. When the cellulose derivative of the present disclosure is produced using cellulose as a raw material that is relatively difficult to butyrate due to its high crystallinity or other reasons, it is preferable to use acetic acid as a cellulose activation treatment agent or a medium for the acylation reaction performed as a pretreatment, and the resulting cellulose derivative has an acetyl group introduced therein.

[0034] Alternatively, when commercially available cellulose acetate butyrate (cellulose acetate butyrate) is used as a raw material and some of its butyryl groups and acetyl groups are hydrolyzed to obtain the cellulose derivative of the present disclosure, the use of acetic acid as a medium for such hydrolysis reaction results in acetyl groups remaining in the obtained cellulose derivative or being introduced therein.

[0035] As described above, the cellulose derivative of the present disclosure preferably has an equal degree of butyryl substitution and a total degree of substitution, and preferably has an acetyl substitution degree of 0. However, when the cellulose derivative is substituted with an acetyl group, the degree of acetyl substitution is preferably more than 0 and not more than 2.5, and more preferably 0.1 or more and 1.0 or less.

[0036] Here, when a cellulose derivative is substituted only with butyryl groups, the cellulose derivative is called cellulose butyrate (or cellulose butyrate), and when the substituents of the cellulose derivative are substituted with acetyl groups in addition to butyryl groups, the cellulose derivative is called cellulose acetate butyrate (or cellulose acetate butyrate or acetated butyrate).

[0037] The degree of substitution of a cellulose derivative can be measured by the following method. For example, it can be measured by NMR according to the method of Tezuka (Tezuka, Carbonydr. Res. 273, 83 (1995)). That is, the free hydroxyl groups of the cellulose derivative are acylated with a carboxylic anhydride in pyridine. The type of carboxylic anhydride used here should be selected according to the purpose of the analysis. For example, when analyzing the degree of butyryl substitution of cellulose butyrate, acetic anhydride is suitable. In addition, when analyzing the degree of butyryl substitution of cellulose acetate butyrate, acetic anhydride is suitable, and when analyzing the degree of acetyl substitution, butyric anhydride is suitable. The obtained sample is dissolved in deuterated chloroform, and 13Measure the C-NMR spectrum. For example, when the substituent is an acetyl group or a butyryl group, the carbon signals of the acetyl group appear in the region from 169 ppm to 171 ppm in the order of 2nd, 3rd, and 6th from the high magnetic field, and the carbon signals of the butyryl group appear in the region from 171 ppm to 173 ppm in the order of 2nd, 3rd, and 6th from the high magnetic field. For another example, when a cellulose derivative having a propionyl group or a cellulose derivative not having a propionyl group is treated with propionic anhydride for analytical purposes and the propionyl substitution degree is analyzed, the signals of the carbonyl carbon of the propionyl group appear in the same order in the region from 172 ppm to 174 ppm. The total degree of substitution of a cellulose derivative treated with carboxylic anhydride by Tezuka's method or a method similar thereto is 3.0, so if the sum of the areas of the carbonyl carbon signals of the acyl groups originally possessed by the cellulose derivative and the carbonyl signals of the acyl groups introduced by the carboxylic anhydride treatment is normalized to 3.0, and the abundance ratios of acetyl groups, butyryl groups, and propionyl groups at the corresponding positions (in other words, the area ratios of each signal) are calculated, this can be taken as the degrees of acetyl, butyryl, or propionyl substitution at the 2nd, 3rd, and 6th positions of the glucose ring in the cellulose derivative. Needless to say, the only substituents containing acyl groups that can be analyzed by this method are those that do not correspond to the carboxylic anhydride used in the treatment for the purpose of analysis. In addition, 13 In addition to C-NMR, 1 It can also be analyzed by H-NMR.

[0038] However, when the total substitution degree at the 2nd, 3rd and 6th positions of the glucose ring of the sample cellulose derivative is 3.0 and it is known in advance that all of the substituents are limited substituents such as acetyl and butyryl groups, the propionylation step can be omitted and the sample can be directly dissolved in deuterated chloroform to measure the NMR spectrum. If all of the substituents are acetyl and butyryl groups, the carbon signals of the acetyl groups appear in the 2nd, 3rd and 6th positions from the high magnetic field in the region from 169 ppm to 171 ppm, and the carbon signals of the butyryl groups appear in the same order in the region from 171 ppm to 173 ppm, as in the case of including the propylation step. Therefore, the substitution degrees of acetyl and butyryl at the 2nd, 3rd and 6th positions of the glucose ring in the cellulose derivative can be obtained from the abundance ratio of the acetyl groups and butyryl groups at the corresponding positions (in other words, the area ratio of each signal).

[0039] The method for producing the cellulose derivative of the present disclosure is not particularly limited, but for example, it can be produced as follows. First, the cellulose derivative substituted only with an aliphatic acyl group other than a butyryl group or other substituent, or other cellulose derivative having a butyryl group can be used as a raw material, and the raw material cellulose or cellulose derivative can be reacted with butyric anhydride or butyric acid chloride in an organic solvent in the presence of a catalyst. Examples of the organic solvent include acetic acid, acetone, pyridine, N,N-dimethylacetamide (DMAc), and a DMAc solution of lithium chloride, as well as mixed solvents thereof. Among these, a solvent containing at least acetic acid is preferred. Examples of the catalyst include sulfuric acid, pyridine, N,N-dimethyl-4-aminopyridine, and the like.

[0040] Secondly, it can be produced by using natural cellulose as a raw material, optionally activating the cellulose, acylating the cellulose with an acylating agent in the presence of a sulfuric acid catalyst, optionally partially neutralizing and deacylating (hydrolysis or aging). More specifically, it can be produced by activating cellulose such as acetic acid, propionic acid, and butyric acid with an organic carboxylic acid corresponding to the acyl group (butyric acid in the case of substitution with a butyryl group), preparing a triacyl ester with an acylating agent such as acetic anhydride, propionic anhydride, and butyric anhydride (butyric anhydride in the case of butylation) using a sulfuric acid catalyst, decomposing the acid anhydride, and adjusting the degree of acylation by hydrolysis or aging in a carboxylic acid / water system.

[0041] Examples of natural cellulose as a raw material include wood pulp and cotton linters. The weight-average degree of polymerization of these natural celluloses is about 1,500 to 3,000 or about 3,000 to 6,000, respectively. When the cellulose derivative of the present disclosure is prepared using natural cellulose as a raw material as described above, the weight-average degree of polymerization decreases during the preparation process and may be about 50 to 1,500. The weight-average degree of polymerization of the cellulose derivative of the present disclosure is not particularly limited, but from the viewpoint of, for example, the stirring load in various reaction operations when preparing the cellulose derivative and the amount of precipitating agent used in the precipitation operation after the aging process, the weight-average degree of polymerization is preferably about 100 to 400.

[0042] [Th1 enhancer] In the Th1 enhancer of the present disclosure, Th1 refers to T cells that predominantly produce interferon gamma (IFN-γ) and are differentiated from naive T cells. Th1 is typically a transcription factor T-bet positive CD4 positive T cell.

[0043] In the Th1-increasing agent of the present disclosure, the term "increase" includes the differentiation of naive T cells into Th1 cells, and the proliferation and / or accumulation of Th1 cells induced by the differentiation. The increase includes an increase in any of in vivo, in vitro, and ex vivo systems.

[0044] Administration of the Th1 enhancer increases Th1 in the intestinal tract. The effect of administration of the Th1 enhancer can be evaluated as follows. Among lymphocytes isolated from an experimental animal such as a mouse orally administered with the Th1 enhancer, CD3- and CD4-positive cells expressing T-bet are labeled as Th1 in the present disclosure, and the ratio of Th1 can be measured by flow cytometry, with the total number of isolated lymphocytes taken as 100.

[0045] The mechanism by which Th1 in the intestinal tract is increased by administration, particularly oral administration, of the Th1 enhancer is as follows. The cellulose derivative of the present disclosure, which is the active ingredient of the Th1 enhancer, is not decomposed by mammalian digestive enzymes, but is fermented or decomposed in part or in whole by intestinal bacteria. The products of the fermentation and decomposition of the cellulose derivative by intestinal bacteria are thought to be butyric acid derived from butyryl groups, and short-chain fatty acids (SCFAs) such as acetic acid, propionic acid, and butyric acid derived from glucose residues. Of these, butyric acid in particular increases preferentially.

[0046] The cellulose derivative of the present disclosure has the characteristic of liberating butyric acid in the intestine and increasing the butyric acid concentration through a mechanism such as being decomposed by intestinal bacteria.

[0047] In contrast to the probiotic approach of directly administering specific bacteria as described in Patent Document 2, the administration of the Th1 enhancer of the present disclosure utilizes ingenuity in the use of cellulose as dietary fiber to provide butyric acid in the intestine, and is, in a sense, a prebiotic approach that addresses the environmental side of intestinal bacteria.

[0048] Here, probiotics and prebiotics are not in conflict with each other, but are expected to have synergistic effects or to have complementary effects, such as one being effective in a situation where the other is ineffective.

[0049] The Th1 enhancer of the present disclosure can take a prebiotic approach. The Th1 enhancer of the present disclosure has the characteristics that the active ingredient can be easily stored and that there are a wide range of options for the form of administration. For example, the Th1 enhancer of the present disclosure can be stored at room temperature for about one year, and can be used as an ingredient in foods baked at temperatures below 200°C, such as bread, cakes, and biscuits.

[0050] The Th1 enhancer of the present disclosure may be contained in food or medicine, and can be used as a component of various foods or medicines as described below, and its administration method includes oral administration in particular. Various forms can be selected. For example, ordinary pharmaceutical forms such as powders, granules, tablets, sugar-coated tablets, capsules, syrups, pills, suspensions, liquids and emulsions, as well as ordinary food forms such as beverages; confectionery products such as gum, chocolate, candy, yokan, and jelly; noodles; baked foods such as bread, cakes, and biscuits; canned foods; retort foods; meat foods; fish paste foods; edible oil compositions such as margarine, dressing, and mayonnaise; dietary supplements; milk products such as butter, ice cream, and yogurt; etc. can be adopted. Among these, the dosage for obtaining the effect in humans is preferably 1g to 10g per day, and sugar-coated tablets; noodles; baked foods such as biscuits, etc. are preferred because they allow for relatively large intakes. The Th1 enhancer of the present disclosure can also be incorporated into pharmaceutical or food formulations as a thickening agent.

[0051] For foods containing the Th1 enhancer of the present disclosure, the content of the cellulose derivative is preferably 0.5% by weight or more, more preferably 1% by weight or more and 5% by weight or less, and even more preferably 1.5% by weight or more and 3% by weight or less. By setting the amount of the Th1 enhancer in the food within the above range, Th1 can be increased without impairing the taste or texture of the food.

[0052] Specific examples of target diseases that are useful for the prevention and / or treatment (reduction or prevention of adverse effects) when the Th1 enhancer of the present disclosure is contained in a food or medicine include the following, which are allergic diseases, infectious diseases, and rejection reactions in organ transplants: sprue, type 1 diabetes, graft-versus-host rejection following bone marrow transplantation, osteoarthritis, juvenile chronic arthritis, Lyme disease arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, insulin-dependent diabetes mellitus, thyroiditis, asthma, psoriasis, scleroderma dermatitis, and the like. scleroderma), atopic dermatitis, graft-versus-host rejection, acute or chronic immune disorders associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves' disease (Pascedou's disease), nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Scholein purpura, microscopic vasculitis of the kidney, chronic active hepatitis, uveitis, septic shock, toxic Shock syndrome, septic syndrome, cachexia, acquired immune deficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, polyglandular deficiency syndrome type 1 and polyglandular deficiency syndrome type 2, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, chlamydia infection, Yersinia and Salmonella infection-related arthropathy, spondyloarthropathy, atherosclerosis / arteriosclerosis, allergic colitis, atopic allergy, food allergy (peanut allergy, tree nut allergy, egg allergy, milk allergy, soy allergy, wheat allergy, seafood allergy, shellfish allergy, sesame allergy, etc.), pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, Coombs test positive hemolytic anemia, acquired pernicious anemia, juvenile malignant anemia anemia, myositis / Royal-Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, acquired immune deficiency syndrome, acquired immune deficiency-related disease, hepatitis C, common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, fibrotic lung disease, idiopathic fibrosing alveolitis, postinflammatory interstitial pneumonia, interstitial pneumonia, connective tissue disease-associated interstitial lung disease, mixed connective tissue-associated lung disease, systemic sclerosis-associated interstitial lung disease,Rheumatoid arthritis-related interstitial lung disease, systemic lupus erythematosus-related lung disease, dermatomyositis / polymyositis-related lung disease, Sjogren's disease-related lung disease, ankylosing spondylitis-related lung disease, vasculitic diffuse lung disease, hemosiderosis-related lung disease, drug-induced interstitial lung disease, radiation fibrosis, obliterative bronchiolitis, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, post-infectious interstitial pneumonia, gouty arthritis, type B insulin resistance due to acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, idiopathic leukopenia, renal disease NOS, glomerulonephritis, microscopic vasculitis in the kidney, discoid lupus erythematosus, idiopathic male infertility or NOS, multiple sclerosis ( (for all subtypes), insulin-dependent diabetes mellitus, sympathetic ophthalmia, connective tissue disease due to pulmonary hypertension, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Takayasu's disease / arteritis, idiopathic thrombocytopenia, hyperthyroidism, goiter hypothyroidism (Hashimoto's disease), primary myxedema, phacogenic uveitis, primary vasculitis, vitiligo, allergic rhinitis (pollen allergy), anaphylaxis, pet allergy, latex allergy, drug allergy, allergic rhinitis conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, cutaneous lupus erythematosus, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, diarrhea, and tumors.

[0053] Th1 produces cytokines such as interferon-γ (IFN-γ) and interleukin (IL)-2. Increase in Th1 is expected to be useful for preventing and treating infectious diseases, inflammation, tumors, etc. through the production of cytokines such as IFN-γ in the body. Increase in Th1 in the intestinal tract such as the small intestine, large intestine, cecum, colon, rectum, etc., particularly in the lamina propria of the large intestine, is useful for preventing and / or treating tumors and allergies such as food allergies.

[0054] The dosage of the Th1 enhancer of the present disclosure is administered to an individual in an amount sufficient to bring about a desired Th1 increase. Specifically, it can be empirically determined in consideration of the individual's age, body weight, sex, health condition, and conditions of the stomach, small intestine, large intestine, etc., administration method, and formulation form. The amount in one administration may be, for example, 12.5 mg / kg body weight to 125 mg / kg body weight, or 25 mg / kg body weight to 75 mg / kg body weight. In addition, it may be administered once to an individual, or may be administered more than once. When administered more than once, it may be administered periodically, irregularly, or as needed. The appropriate number of administrations can be empirically determined in consideration of the individual's conditions, administration method, and formulation form, etc., as well as the dosage. EXAMPLES

[0055] The present invention will be described in detail below with reference to examples, but the technical scope of the present invention is not limited to these examples.

[0056] [Preparation of cellulose derivatives] (Preparation of Regenerated Cellulose (Base-Catalyzed Deesterification of Cellulose Acetate Butyrate)) 1.5 kg of sodium hydroxide was added to 29.0 L of deionized water and dissolved. The gas phase in the vessel was conditioned with nitrogen, and 2.0 kg of cellulose acetate butyrate (Sigma-Aldrich, product number 419060; hereinafter referred to as "raw cellulose acetate butyrate") was added as a raw material, followed by slow addition of 7.0 L of methanol. The mixture was stirred and held at 30°C for 72 hours. Then, acetic acid was added to adjust the pH to 6.2 to 7. The solid matter obtained was filtered and washed with 75 L of deionized water, and then dried under reduced pressure at 80°C to obtain 880.0 g of white powder. This was designated Cell-WSCB. As shown in the "Measurement of Substitution Degree" below, the acetyl substitution degree of the raw cellulose acetate butyrate was 0.1, the butyryl substitution degree was 2.5, and the total substitution degree was 2.6, and Cell-WSCB is a regenerated cellulose that does not have an acetyl group or a butyryl group.

[0057] (Dissolution of Cell-WSCB (regenerated cellulose)) 850.0g of Cell-WSCB (regenerated cellulose) was suspended in a deionized water / methanol mixture (3.4L / 1.7L), left to stand for 30 minutes, and the liquid phase was filtered off. The obtained wet regenerated cellulose was suspended in 5.7L of dimethylacetamide (DMAc), left to stand for 30 minutes, and the liquid phase was filtered off. This operation was repeated four times to remove water from the wet regenerated cellulose. 1.2kg of lithium chloride and 15.0L of DMAc were added to the obtained wet regenerated cellulose, and the temperature was raised to 100°C under a nitrogen atmosphere and held for 1 hour. The mixture was cooled to near room temperature, further cooled to -20°C using dry ice and held for 1 hour, and then heated to near room temperature. A transparent regenerated cellulose solution was obtained.

[0058] (Preparation of cellulose butyrate (WSCB)) To the obtained regenerated cellulose solution, 1.1L of pyridine was added under a nitrogen atmosphere, and 1.221L of butyric anhydride was slowly added. Then, the temperature was raised to 90°C and maintained for 5 hours. After that, the temperature was lowered to 50°C, and 1.0L of ethanol was slowly added to obtain a reaction mixture. At this time, the temperature of the mixture rose due to the rise in temperature due to the decomposition of the anhydride, but the rate of addition of ethanol was adjusted so that the temperature was always 75°C or less. The obtained reaction mixture was slowly added to a mixture of 110L of tetrahydrofuran (TFH) and deionized water (volume ratio 1 / 1) to form a precipitate. The precipitate was washed with 30L of deionized water and 30L of ethanol in sequence. It was dried under reduced pressure at 80°C to obtain 925.0g of a product. This is called WSCB. As shown in the "Measurement of Substitution Degree" later, WSCB is a butyric acid cellulose with an acetyl substitution degree of 0.0, a butyryl substitution degree of 1.3, and a total substitution degree of 1.3.

[0059] [Measurement of substitution degree] (Measurement of the substitution degree of raw cellulose acetate butyrate) (1) Acetylation of raw cellulose acetate butyrate 1.2g of raw cellulose acetate butyrate was dissolved in 12mL of DMAc. 12mL of pyridine, 90mg of N,N-dimethylaminopyridine, and 12mL of acetic anhydride were added to this solution, and the mixture was heated to 100℃ under stirring under nitrogen atmosphere and maintained for 1 hour. The reaction mixture was cooled to near room temperature and added to 600mL of a mixed solvent of methanol / deionized water (volume ratio 1 / 1) to form a precipitate, which was then drained. The precipitate was washed three times with 60mL of a mixed solvent of the same composition. The precipitate was dissolved in 30mL of acetone. The acetone solution of the precipitate was added to 600mL of a mixed solvent of methanol / deionized water (volume ratio 1 / 1) to form a precipitate, which was then drained. The precipitate was washed three times with 60mL of a mixed solvent of the same composition. The mixture was then dried under reduced pressure at 80℃ to obtain a powdered sample. The obtained sample was acetylated raw cellulose acetate butyrate. This is called AN020.

[0060] The total degree of substitution of acetyl groups and butyryl groups in AN020 is 3.0. That the total degree of substitution of acetyl groups and butyryl groups is 3.0, in other words, that there is no unsubstituted hydroxyl group, was verified by the fact that when a sample obtained by acylation (acetylation) was acylated a second time under the same conditions, the ratio of acetyl groups to butyryl groups (or the respective degrees of substitution of acetyl groups and butyryl groups calculated on the assumption that the total degree of substitution is 3.0) did not change before and after the second acylation.

[0061] The obtained AN020 was dissolved in deuterated chloroform. 13C-NMR spectrum was measured. The results are shown in Figure 1. The acetyl and butyryl group signals at the 2nd, 3rd, and 6th positions of the glucose residue are called Ac2, Ac3, Ac6, Bu2, Bu3, and Bu6, respectively. The carbon signals of the acetyl group appear in the region from 169 ppm to 171 ppm in the order of 2nd, 3rd, and 6th positions from the high magnetic field, and the carbon signals of the butyryl group appear in the same order in the region from 171 ppm to 173 ppm, so Ac2, Ac3, Ac6, Bu2, Bu3, and Bu6 are the signals as shown in Figure 1. The sum of the areas of these signals was set to 3.0, and the ratio of the sum of the areas of Ac2, Ac3, and Ac6 to the sum of the areas of Bu2, Bu3, and Bu6 in this sum was calculated, and these were taken as the degree of acetyl substitution and the degree of butyryl substitution, respectively. As a result, the degree of butyryl substitution was 2.5.

[0062] (2) Butyrylation of raw cellulose acetate butyrate A powdered sample was obtained in the same manner as in (1) above (acetylation of raw cellulose acetate butyrate), except that 12 mL of acetic anhydride was replaced with 18 mL of butyric anhydride. This was designated AN021. AN021 was obtained by butyrylation of raw cellulose acetate butyrate.

[0063] The total degree of substitution of acetyl and butyryl groups in AN021 is also 3.0. That the total degree of substitution of acetyl and butyryl groups is 3.0, in other words, that there is no unsubstituted hydroxyl group, was verified by the fact that when a sample obtained by acylation (butyrylation) was acylated (butyrylated) again under the same conditions, the ratio of acetyl and butyryl groups (or the respective degrees of substitution of acetyl and butyryl groups calculated on the assumption that the total degree of substitution is 3.0) did not change before and after the second acylation.

[0064] For AN021, as with AN020, 13C-NMR spectrum was measured. The results are shown in Figure 1. The sum of the areas of the signals Ac2, Ac3, Ac6, Bu2, Bu3, and Bu6 was set to 3.0, and the ratio of the sum of the areas of Ac2, Ac3, and Ac6 to the sum of the areas of Bu2, Bu3, and Bu6 in this sum was calculated and determined as the degree of acetyl substitution and the degree of butyryl substitution, respectively. As a result, the degree of acetyl substitution was 0.1.

[0065] (3) Degree of acetyl substitution and degree of butyryl substitution Since the starting cellulose acetate butyrate has an acetyl group, a butyryl group, and an unsubstituted hydroxyl group, the butyryl substitution degree of AN020 obtained by acetylating the unsubstituted hydroxyl group is equal to the butyryl substitution degree of the starting cellulose acetate butyrate. The acetyl substitution degree of AN021 is also equal to the acetyl substitution degree of the starting cellulose acetate butyrate. Therefore, the acetyl substitution degree of the starting cellulose acetate butyrate is 0.1, the butyryl substitution degree is 2.5, and the total substitution degree is 2.6.

[0066] (Measurement of the degree of substitution of Cell-WSCB) (1) Acetylation of Cell-WSCB 1.6g of Cell-WSCB was suspended in 100mL of deionized water, left to stand at room temperature for 30 minutes, and dehydrated with a glass filter (G3) to obtain wet Cell-WSCB. This wet Cell-WSCB was suspended in 60mL of DMAc, left to stand at room temperature for 30 minutes, and dehydrated with a glass filter (G3). This series of operations was repeated five times, and 24mL of DMAc and 2.4g of lithium chloride were added to the obtained wet Cell-WSCB, and the mixture was heated to 100°C under a nitrogen atmosphere while stirring and held for 1 hour. This mixture was cooled to near room temperature, further cooled to -20°C using dry ice and held for 1 hour, and then heated to near room temperature, resulting in a transparent solution. 24ml of pyridine, 180mg of N,N-dimethylaminopyridine, and 24mL of acetic anhydride were added to this solution, and the mixture was heated to 100°C under a nitrogen atmosphere while stirring and held for 8 hours, and then allowed to cool to near room temperature. This reaction mixture was added to 1,200 mL of a mixed solvent of methanol and deionized water (volume ratio 1 / 1) to form a precipitate, which was then drained. The precipitate was washed three times with 120 mL of a mixed solvent of the same composition. The resulting precipitate was dissolved in 60 mL of acetone. Note that this dissolution process involved cooling to -20°C and then heating to around room temperature. The acetone solution of the precipitate was added to 1,200 mL of a mixed solvent of methanol and deionized water (volume ratio 1 / 1) to form a precipitate, which was then drained. The precipitate was washed three times with 120 mL of a mixed solvent of the same composition, and then dried under reduced pressure at 80°C to obtain a powdered sample. This was designated AN009.

[0067] The obtained AN009 was dissolved in deuterated chloroform, and the same procedure as for AN020 was carried out. 13 The C-NMR spectrum was measured, and the results are shown in Figure 2. No signal corresponding to a butyryl group was observed in the spectrum of AN009.

[0068] (2) Butyrylation of Cell-WSCB A powdered sample was obtained in the same manner as in (1) Acetylation of Cell-WSCB, except that 24 mL of acetic anhydride was replaced with 38 mL of butyric anhydride. This was designated AN013. AN013 is a butyrylated version of Cell-WSCB (regenerated cellulose).

[0069] The obtained AN013 was dissolved in deuterated chloroform, and the same procedure as for AN020 was carried out. 13 The C-NMR spectrum was measured, and the results are shown in Figure 2. No signal corresponding to an acetyl group was observed in the spectrum of AN013.

[0070] (3) Degree of acetyl substitution and degree of butyryl substitution The butyryl substitution degree of the obtained AN009 is 0. Since the series of processes for obtaining AN009 from CELL-WSCB does not include a process for adding or removing a butyryl group, the butyryl substitution degree of the obtained AN009 is equal to the butyryl substitution degree of Cell-WSCB (regenerated cellulose). In other words, the butyryl substitution degree of Cell-WSCB (regenerated cellulose) is 0.

[0071] The degree of acetyl substitution of the obtained AN013 was 0. The degree of acetyl substitution of AN013 was also equal to that of Cell-WSCB. Therefore, the degree of acetyl substitution of Cell-WSCB was 0. Therefore, the degree of acetyl substitution of Cell-WSCB obtained by base-catalyzed deesterification of the raw cellulose acetate butyrate was 0, and the degree of butyryl substitution was 0. In other words, it was confirmed that Cell-WSCB is a regenerated cellulose.

[0072] (Measurement of the degree of substitution of cellulose butyrate (WSCB)) Except for replacing the raw cellulose acetate butyrate with cellulose butyrate (WSCB), cellulose butyrate (WSCB) was acetylated in the same manner as in (1) above, to obtain a powdered sample designated AN004.

[0073] The obtained AN004 was dissolved in deuterated chloroform, and the same procedure as for AN020 was carried out. 13 The C-NMR spectrum was measured, and the results are shown in Figure 3.

[0074] Since Cell-WSCB does not have an acetyl group, all of the acetyl groups shown in the spectrum of AN004 are believed to have been introduced by subsequent acetylation. On the other hand, all of the butyryl groups shown in the spectrum of AN004 are believed to be derived from WSCB. The total degree of substitution of the acetyl and butyryl groups in AN004 is also 3.0. The sum of the areas of the signals of Ac2, Ac3, Ac6, Bu2, Bu3, and Bu6 was set to 3.0, and the ratio of the sum of the areas of Ac2, Ac3, and Ac6 to the sum of the areas of Bu2, Bu3, and Bu6 in this sum was calculated, and these were taken as the degree of acetyl substitution and the degree of butyryl substitution, respectively. The degree of butyryl substitution was 1.3.

[0075] The process for obtaining AN004 from WSCB does not include any process for adding or removing butyryl groups, so the butyryl substitution degree of the obtained AN004 is equal to that of cellulose butyrate (WSCB), which is therefore 1.3.

[0076] (Measurement of polymerization degree of cellulose butyrate (WSCB)) The polystyrene equivalent molecular weight (weight average molecular weight and number average molecular weight) of AN004 obtained by acetylating WSCB using the above method was measured by GPC (SEC), and the polymerization degree (weight average polymerization degree and number average polymerization degree) was calculated based on the following formula, which was used as the polymerization degree of WSCB. Degree of polymerization = molecular weight ÷ (162.14 + degree of butyryl substitution × 70.091 + (degree of 3-butyryl substitution) × 42.037) Molecular weight: weight average molecular weight or number average molecular weight

[0077] The GPC measurements were carried out under the following conditions. Solvent: Tetrahydrofuran Sample concentration: 0.2% (wt / vol) Columns: Shodex KF-804 and KF-805 Temperature: 30℃ Flow rate: 1ml / min Sample injection volume: 50 μl Detection: Differential refractive index detector Standard polystyrene: Shodex SM-105 (molecular weights: 2,700,000, 1,390,000, 661,000, 323,000, 124,000, 47,200, 18,300, 6,940, 2,980, and 1,220)

[0078] The weight-average degree of polymerization of WSCB thus determined was 254, and the number-average degree of polymerization was 128.

[0079] [Evaluation of Th1 increase] (Feed preparation) The purified diet AIN-93G (REEVE et al., Journal of Nutrition, 123, 1939-1951 (1993)) contains 5% by weight of cellulose, and the diet in which all of the cellulose was replaced with WSCB (hereinafter referred to as WSCB-AIN-93G) was used as the butyric acid diet. The diet in which all of the cellulose was replaced with Cell-WSCB (hereinafter referred to as Cell-WSCB-AIN-93G) was used as the normal diet.

[0080] (Laboratory animals) Three-week-old male C57BL / 6J mice were used.

[0081] (Breeding experiment) Ten mice were fed Cell-WSCB-AIN-93G and bred for one week (preliminary breeding). After that, the mice were divided into two groups of five mice each and bred for another four weeks. At this time, one group was fed Cell-WSCB-AIN-93G and was designated the normal diet group. The remaining group was fed WSCB-AIN-93G and was designated the butyric acid diet group. All mice were allowed to consume food ad libitum.

[0082] (Cell Separation and Flow Cytometry) To isolate lymphocytes from the colonic lamina propria of mice, the colon was collected, cut open longitudinally, and washed to remove feces, etc. The washed colon was then shaken in HBSS containing 5 mM EDTA at 37°C for 20 minutes. After removing epithelial cells and adipose tissue, the intestinal tissue was cut into small pieces and incubated in RPMI 1640 medium (2% fetal bovine serum (FBS), 400 U / ml collagenase D (Roche Diagnostics), 0.25 U / ml dispase (Corning), and 0.1 mg / ml DNase I (Wako)) for 1 h in a water bath at 37°C. The digested tissue was washed with HBSS containing 5 mM EDTA, resuspended in 5 ml 35% Percoll (GE Healthcare), and layered on top of 2.5 ml 70% Percoll in a 15 ml Falcon tube. The tissue was then centrifuged at 2000 rpm for 20 min at room temperature to separate cells using a Percoll density gradient. The cells at the interface were collected and used as lamina propria lymphocytes.

[0083] (Th1 staining) The collected cells were suspended in staining buffer (PBS, 2% FBS) and stained with PerCP / Cy5.5-labeled anti-CD3e antibody (145-2C11, Biolegend) and APC-eflour780-labeled anti-CD4 antibody (RM4-5, eBiosciences). After staining for CD3e and CD4, intracellular Foxp3 and T-bet were stained using Foxp3 Staining Buffer Set (eBioscience), PE-labeled anti-Foxp3 antibody (FJK-16s, eBioscience), and PE / cy7-labeled anti-T-bet antibody (4B-10, Biolegend).

[0084] (INF-γ production stimulation and staining) To examine the production ability of INF-γ, a major cytokine of Th1, the collected cells were added to RPMI 1640 medium (10% FBS (Roche), 0.1 mM HEPES, 100 unit / ml penicillin, 100 μg / ml streptomycin, 2 mM L-glutamine and 0.1 mM 2-mercaptoethanol (all Thermo Fisher Scientific)) supplemented with 25 ng / ml PMA, 1 μg / ml ionomycin (both from Sigma-Aldrich), and 5 μg / ml Brefeldin A Solution (Biolegend) and cultured in a CO2 incubator at 37°C for 4 hours. After washing, the cells were suspended in staining buffer (PBS, 2% FBS) and stained with PerCP / Cy5.5-labeled anti-CD3e antibody (145-2C11, Biolegend) and APC-eflour780-labeled anti-CD4 antibody (RM4-5, eBiosciences). After staining for CD3e and CD4, intracellular INF-γ staining was performed using Foxp3 Staining Buffer Set (eBioscience) and FITC-labeled anti-IFN-γ antibody (XMG1.2, Biolegend).

[0085] Flow cytometry was performed using a FACScant II, and data were analyzed using FlowJo software (TreeStar Inc.).

[0086] (Flow cytometry results for Th1) The flow cytometry results are shown in Figure 4. Among the CD3e-positive and CD4-positive helper T cells, cells that did not express Foxp3 but expressed T-bet were defined as Th1 cells. The proportion of Th1 cells was high in the butyric acid diet group, at 10.3% in the normal diet group and 24.5% in the butyric acid diet group.

[0087] The results of quantitative evaluation of Th1 cells based on flow cytometry are shown in Figure 5. The total number of lamina propria lymphocytes was taken as 100, and the proportion of Th1 cells among lamina propria lymphocytes was approximately 1.5% in the normal diet group and approximately 3.5% in the butyric acid diet group, showing a higher ratio in the butyric acid diet group. The number of Th1 cells was approximately 5.5 × 10 in the normal diet group. 4 1.5×10 in the butyric acid diet group 5 The butyric acid diet group had a higher number of schizophrenia patients than the non-butyric acid diet group.

[0088] As described above, simply replacing 5% by weight of the purified diet with WSCB was sufficient to increase Th1.

[0089] (Flow cytometry results for INF-γ producing cells) The flow cytometry results are shown in Figure 6. Among the CD3e-positive CD4-positive helper T cells, cells expressing INF-γ were defined as INF-γ-producing cells. The proportion of such cells was high in the butyric acid diet group, at 4.8% in the normal diet group and 10.7% in the butyric acid diet group.

[0090] The results of quantitative evaluation of INF-γ-producing cells based on flow cytometry are shown in Figure 7. The total number of lamina propria lymphocytes was taken as 100, and the proportion of INF-γ-producing cells among lamina propria lymphocytes was approximately 0.5% in the normal diet group and approximately 1.6% in the butyric acid diet group, indicating a higher proportion in the butyric acid diet group. The number of Th1 cells was approximately 2.5 × 10 in the normal diet group. 4 , and 7.5 × 10 4 The butyric acid diet group had a higher number of schizophrenia patients than the non-butyric acid diet group.

[0091] As described above, simply replacing 5% by weight of the purified diet with WSCB increased the number of cells producing INF-γ, the main cytokine of Th1.

[0092] [Evaluation of the contribution of gut bacteria to Th1 proliferation] (Feed preparation) Cell-WSCB-AIN-93G (normal diet) and WSCB-AIN-93G (butyric acid diet) were prepared in the same manner as in the evaluation of Th1 expansion.

[0093] (Laboratory animals) Three-week-old male C57BL / 6J mice were used.

[0094] (Breeding experiment) Fifteen mice were fed Cell-WSCB-AIN-93G and bred for one week (preliminary breeding). After that, the mice were divided into three groups of five mice each and bred for another four weeks. At this time, one group was fed Cell-WSCB-AIN-93G (normal diet) and water. One group was fed Cell-WSCB-AIN-93G (normal diet) and antibiotics (vancomycin, neomycin, ampicillin, and metronidazole (all from Wako) in drinking water). The other group was fed WSCB-AIN-93G (butyric acid diet) and antibiotics (vancomycin, neomycin, ampicillin, and metronidazole in drinking water). Since it is possible to effectively reduce intestinal bacteria and suppress fluctuations by administering four types of antibiotics, we verified whether the increase in Th1 was due to WSCB and not due to changes in intestinal bacteria. Food and water were freely available.

[0095] (Sample collection) Th1 distal colons were collected from three groups of mice: normal diet + water, normal diet + antibiotics, and butyric acid diet + antibiotics, and stored in RNAlater (Thermo Fisher Scientific). Samples were disrupted with stainless steel beads, and RNA was extracted using an RNeasy Mini Kit (Qiagen). Reverse transcription PCR was then performed using random primers and ReverTra Ace (both from Toyobo Life Sciences).

[0096] (Quantitative PCR) The expression level of the Tbx21 gene, which encodes T-bet, in the distal colon was evaluated by quantitative PCR. Specifically, quantitative PCR was performed using a Light Cycler 480 (Roche), and the relative expression level of Tbx21 to the housekeeping gene β-actin (Actb) was calculated using the comparative Ct method.

[0097] The expression level of the Infg gene, which encodes interferon-gamma (IFN-γ), in the distal colon was evaluated by quantitative PCR. Specifically, quantitative PCR was performed using a Light Cycler 480 (Roche), and the relative expression level of Infg to the housekeeping gene β-actin (Actb) was calculated using the comparative Ct method.

[0098] (Quantitative PCR results) The quantitative PCR results are shown in Figure 8. The relative expression level of the Tbx21 gene in the distal colon was significantly higher in the butyric acid diet group than in the normal diet group, even under antibiotic administration. In addition, the relative expression level of the Infg gene, which encodes IFN-γ, was significantly higher in the butyric acid diet group than in the normal diet group, even under antibiotic administration. The presence or absence of significant differences was evaluated by one-way analysis of variance (one-way ANOVA) followed by Tukey's test. These results suggest that WSCB induces Th1, regardless of changes in the intestinal flora.

Claims

1. A type 1 helper T cell-increasing agent for preventing infectious diseases through the production of cytokines in the intestinal tract by type 1 helper T cells, comprising as an active ingredient a cellulose derivative having a butyryl substitution degree of 0.3 or more and a total substitution degree of 0.5 or more and 2.8 or less.

2. 2. The agent for increasing type 1 helper T cells according to claim 1, wherein the cellulose derivative has a butyryl substitution degree of 0.3 or more and 1.5 or less, and a total substitution degree of 0.5 or more and 1.5 or less.

3. The agent for increasing type 1 helper T cells according to claim 1, wherein the degree of acetyl substitution of the cellulose derivative is more than 0 and not more than 2.

5.

4. The agent for increasing type 1 helper T cells according to claim 1 or 2, wherein the degree of acetyl substitution of the cellulose derivative is 0.

5. The agent for increasing type 1 helper T cells according to any one of claims 1 to 4, wherein the cellulose derivative is cellulose butyrate or cellulose acetate butyrate.

6. A food product for preventing infectious diseases through the production of cytokines in the intestinal tract by type 1 helper T cells, comprising the agent for increasing type 1 helper T cells according to any one of claims 1 to 5.

7. A food product comprising the agent for increasing type 1 helper T cells according to any one of claims 1 to 5, wherein the cellulose derivative is present in an amount of 1% by weight or more and 5% by weight or less.

8. A medicine for preventing infectious diseases through the production of cytokines in the intestinal tract by type 1 helper T cells, comprising the agent for increasing type 1 helper T cells according to any one of claims 1 to 5.

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