Antigen response enhancer

Abstract

To provide an antigen responsiveness enhancer.SOLUTION: An antigen responsiveness enhancer comprises at least one selected from the group consisting of euglena, paramylon, processed paramylon, and β-1,3-glucan.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to antigen response enhancers, etc. [Background technology]

[0002] Organisms possess a defense mechanism against foreign antigens in which antigen-presenting cells, having taken up the foreign antigen, present it to T cells. The T cells that receive the presentation are then activated and proliferate, expressing various immune responses against the foreign antigen. Antigen responsiveness (i.e., the reaction between antigen-presenting cells and T cells), which is the starting point of this defense mechanism, is particularly important.

[0003] On the other hand, it has been reported that as organisms age, the number of senescent T cells and terminally differentiated T cells, which have reduced or lost proliferative capacity after antigen stimulation, increases, while the number of naive T cells and T cells that have not aged significantly, which have high proliferative capacity after antigen stimulation, decreases. For this reason, in order to prevent the decline in immune function due to aging, or to enhance the above-mentioned defense mechanisms regardless of aging, it is particularly important to enhance the antigen responsiveness of naive T cells and T cells that have not aged significantly.

[0004] Euglena is a microalga belonging to the genus Euglena and is used as a food ingredient. Euglena extract is also applied to the skin (Patent Document 1). Paramylon is a β-1,3-glucan produced by Euglena and has been reported to be useful in wound healing and allergy suppression. However, the effects of Euglena and β-1,3-glucan on antigen responsiveness remain unknown. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Special Publication No. 2008-526954 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The object of this invention is to provide an antigen response enhancer. [Means for solving the problem]

[0007] In view of the above problems, the inventors conducted diligent research and found that an antigen response enhancer containing at least one selected from the group consisting of Euglena, paramylon, paramylon processed products, and β-1,3-glucan can solve the above problems. Based on this finding, further research led to the completion of the present invention. That is, the present invention encompasses the following embodiments. That is, the present invention encompasses the following embodiments.

[0008] Item 1. An antigen response enhancer containing at least one selected from the group consisting of Euglena, paramylon, paramylon processed products, and β-1,3-glucan.

[0009] Item 2. The antigen response enhancer according to Item 1, comprising at least one selected from the group consisting of Euglena, paramylon, and paramylon processed products.

[0010] Item 3. An antigen responsiveness enhancer according to item 1 or 2, wherein the Euglena is Euglena gracilis.

[0011] Item 4. An antigen responsiveness enhancer according to any one of items 1 to 3, wherein the Euglena is Euglena gracilis EOD-1 strain (accession number FERM BP-11530).

[0012] Item 5. An immunosenescence inhibitor, which is an antigen responsiveness enhancer as described in any of items 1 to 4.

[0013] Item 6. The antigen responsiveness enhancer according to any one of Items 1 to 5, for use in at least one selected from the group consisting of promotion of an increase in CD28-positive CD57-negative T cells, promotion of an increase in naive T cells, promotion of an increase in CD28 expression in naive T cells, promotion of an increase in CD80 expression in monocytes, promotion of an increase in CD86 expression in monocytes, promotion of an increase in HLA-DR expression in monocytes, promotion of a decrease in CD28-negative CD57-positive T cells, promotion of a decrease in terminally differentiated T cells, promotion of an increase in CD38 expression in monocytes, promotion of an increase in CD38 expression in T cells, promotion of an increase in regulatory T cells, promotion of an increase in interleukin-17A, promotion of an increase in interleukin-17C, and promotion of an increase in granulocyte-macrophage colony-stimulating factor.

[0014] Item 7. The antigen responsiveness enhancer according to any one of Items 1 to 6, which is a food composition, a dietary supplement, a food additive, or a medicament.

[0015] Item 8. The antigen responsiveness enhancer according to any one of Items 1 to 7, which is an oral composition.

[0016] Item 9. An inhibitor of immune aging, comprising at least one selected from the group consisting of Euglena, paramylon, processed paramylon, and β-1,3-glucan.

[0017] Item 10. A composition comprising at least one selected from the group consisting of Euglena, paramylon, processed paramylon, and β-1,3-glucan, for use in at least one selected from the group consisting of promotion of an increase in CD28-positive CD57-negative T cells, promotion of an increase in naive T cells, promotion of an increase in CD28 expression in naive T cells, promotion of an increase in CD80 expression in monocytes, promotion of an increase in CD86 expression in monocytes, promotion of an increase in HLA-DR expression in monocytes, promotion of a decrease in CD28-negative CD57-positive T cells, promotion of a decrease in terminally differentiated T cells, promotion of an increase in CD38 expression in monocytes, promotion of an increase in CD38 expression in T cells, promotion of an increase in regulatory T cells, promotion of an increase in interleukin-17A, promotion of an increase in interleukin-17C, and promotion of an increase in granulocyte-macrophage colony-stimulating factor. [Advantageous Effects of the Invention]

[0018] According to the present invention, an antigen responsiveness enhancer can be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] [Figure 1] Item (1) of Test Example 1-1: shows the measurement results of the proportion (%) of CD28+CD57- CD4+ T cells. Placebo indicates the control diet intake group, and Active indicates the test diet intake group. The vertical axis represents the value obtained by subtracting the measurement value at the start of the test from the measurement value at the end of the test. Each column shows the average value. * indicates a significant difference between groups (P < 0.05, Welch's t-test). [Figure 2] Item (2) of Test Example 1-1: shows the measurement results of the proportion (%) of CD28+CD57- CD8+ T cells. The description of the graph is the same as in Figure 1. [Figure 3] Item (3) of Test Example 1-1: shows the measurement results of the proportion (%) of naive CD4+ T cells. The description of the graph is the same as in Figure 1. [Figure 4] Item (4) of Test Example 1-1: shows the measurement results of the proportion (%) of terminally differentiated CD4+ T cells. The description of the graph is the same as in Figure 1. [Figure 5] Item (9) of Test Example 1-2: shows the measurement results of CD28 expression level in naive CD4+ T cells. Placebo indicates the control diet intake group, and EOD-1 indicates the test diet intake group. The vertical axis represents the value obtained by subtracting the measurement value at the start of the test from the measurement value at the end of the test. Each column shows the average value. * indicates a significant difference between groups (P < 0.05, Welch's t-test). [Figure 6] Item (10) of Test Example 1-2: shows the measurement results of CD28 expression level in naive CD8+ T cells. The description of the graph is the same as in Figure 5. [Figure 7] Item (11) of Test Example 1-3: shows the measurement results of CD80 expression level in monocytes. Placebo indicates the control diet intake group, and EOD-1 indicates the test diet intake group. The vertical axis represents the value obtained by subtracting the measurement value at the start of the test from the measurement value at the end of the test. Each column shows the average value. * indicates a significant difference between groups (P < 0.05, Welch's t-test). [Figure 8] Items (14) to (18) of Study Examples 1-4 show the results of measuring CD38 expression levels in naive CD4+ T cells, CD4+ central memory T cells (Tcm), CD4+ effector memory T cells (Tem), naive CD8+ T cells, and CD8+ terminally differentiated T cells (Temra). In the horizontal axis, SCR represents the start of the study and 12W represents the end of the study, and the vertical axis represents CD38 expression level. The bar in each box represents the median. For both SCR and 12W, the left side represents the control diet group and the right side represents the test diet group. The values ​​at the top of each graph are the p-values ​​when the comparison between the control diet group and the test diet group was evaluated using a linear mixed-effects model with the intervention as a fixed effect and individuals as a random effect, using the lme4 package (v1.1-31) and emmeans package (v1.8.2). [Figure 9] Items (19) to (20) of Test Examples 1-4 show the measurement results of CD38 expression levels in intermediate monocytes and nonclassical monocytes. The explanation of the graphs is the same as in Figure 8. [Figure 10] Item (21) of Study Example 1-5: This shows the measurement results of the percentage of regulatory T cells (Treg) among CD4+ T cells. On the horizontal axis, SCR represents the start of the study and 12W represents the end of the study, and the vertical axis represents the percentage of regulatory T cells among CD4+ T cells. The bar in each box represents the median. For both SCR and 12W, the left side represents the control diet group and the right side represents the test diet group. The value at the top of each graph is the p-value when the comparison between the control diet group and the test diet group was evaluated using a linear mixed-effects model with the intervention as a fixed effect and individuals as a random effect, using the lme4 package (v1.1-31) and emmeans package (v1.8.2). [Figure 11]Items (22) to (24) of Test Examples 1-6: These show the measurement results of serum levels of interleukin-17A (IL17A), interleukin-17C (IL17C), and granulocyte-macrophage colony-stimulating factor (GM-CSF (CSF2)). On the horizontal axis, SCR represents the start of the study and 12W represents the end of the study, while the vertical axis shows the amount of cytokines (unit: pg / mL) shown at the top of the graph. The bar in each box represents the median. For both SCR and 12W, the left side represents the control diet group and the right side represents the test diet group. The "p" at the top of each graph indicates the P-value when comparing the control diet group and the test diet group using the rank sum method with the RankProd package (v3.22.0), and "FC" indicates the magnification change. [Modes for carrying out the invention]

[0020] In this specification, the terms “contains” and “includes” include the concepts of “contains,” “includes,” “substantially consist of,” and “consist solely of.”

[0021] In one aspect, the present invention relates to an antigen response enhancer (which may be referred to as "the agent of the present invention" in this specification) containing at least one selected from the group consisting of Euglena, paramylon, paramylon processed products, and β-1,3-glucan. This will be described below.

[0022] 1. Euglena Euglena is a microalga belonging to the genus Euglena, and is not particularly limited to that extent. Specifically, Euglena includes, for example, Euglena gracilis (Euglena gracilis) Euglena longa , Euglena caudata , Euglena oxyuris , Euglena tripteris , Euglena proxima , Euglena viridis , Euglena sociabilis , Euglena ehrenbergii , Euglena deses , Euglena pisciformis , Euglena spirogyra , Euglena acus , Euglena geniculata , Euglena intermedia , Euglena mutabilis , Euglena sanguinea , Euglena stellata , Euglena terricola , Euglena klebsi , Euglena rubra , Euglena cyclopicola These are some examples. Among these, Euglena gracilis is preferred from the viewpoint of more reliably demonstrating the effects of the present invention, and Euglena gracilis EOD-1 strain is preferred [internationally deposited on June 28, 2013, under the provisions of the Budapest Convention, with accession number FERM BP-11530 at the National Institute of Technology and Evaluation Patent Organism Depositary Center {NITE-IPOD (Room 120, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818)}].

[0023] The form of Euglena is not particularly limited, as long as it contains the majority of the Euglena cell bodies or their components. Examples of Euglena forms include dried powder, suspension, and extract, with dried powder being preferred.

[0024] The paramylon content of Euglena in its dry state is, for example, 50% or more, preferably 60% or more, and more preferably 70% or more.

[0025] Euglena may be used alone or in combination of two or more species.

[0026] 2. β-1,3-glucan, paramylon β-1,3-glucans are not particularly limited as long as they have a single sugar chain (or sugar chain structure) as their main chain, consisting only of glucose units linked by β1,3 bonds. β-1,3-glucans are not limited to linear structures; branched structures are also included.

[0027] The weight-average molecular weight of the β-1,3-glucan derivative is not particularly limited, but for example, 1 × 10⁻⁶ 4 ~2×10 6 Preferably 5 × 10 4~1×10 6 , more preferably 1×10 5 ~1×10 6 . The weight average molecular weight can be measured by GPC method.

[0028] β-1,3-glucan may be obtained by chemical synthesis, but from the viewpoint of easy availability, natural β-1,3-glucan produced by various organisms is preferred. Examples of natural β-1,3-glucan include paramylon, curdlan, laminaran, callose, lentinan, schizophyllan, etc. Among these, paramylon is particularly preferred. Hereinafter, paramylon will be described.

[0029] Paramylon is a Euglena-derived β-1,3-glucan, and is not particularly limited as long as it satisfies this requirement.

[0030] For Euglena from which paramylon is derived, the description is the same as that in the above "1. Euglena".

[0031] The mass average molecular weight of paramylon is not particularly limited, and is, for example, 1×10 4 ~5×10 6 , preferably 2×10 4 ~1×10 6 , more preferably 5×10 4 ~1×10 6 , still more preferably 1×10 5 ~5×10 5 .

[0032] The mass average molecular weight can be measured by SEC-MALS analysis under the following conditions: Detector: multi-angle light scattering detector (DAWN HELEOS II manufactured by Wyatt Technology), differential refractometer detector (Optilab T-rEX manufactured by Wyatt Technology); Column used: two TSKgel α-M columns (manufactured by Tosoh Corporation); Mobile phase: DMSO supplemented with 0.05 M potassium bromide Flow rate: 0.5 mL / min.

[0033] Paramylon typically exists within Euglena cells as paramylon particles, formed by the highly regular accumulation of triple helix structures created by β-1,3-glucan chains.

[0034] The shape of paramylon particles is not particularly limited, but is usually a flattened ellipsoid.

[0035] The particle size distribution of paramylon particles is not particularly limited, but is, for example, 0.5 to 15 μm, preferably 1 to 6 μm. The average particle size of paramylon particles is also not particularly limited, but is, for example, 1 to 10, preferably 2 to 4 μm.

[0036] The form of paramylon is not particularly limited as long as it contains paramylon. Examples of the form of Euglena include dried paramylon powder and paramylon suspension, with dried paramylon powder being preferred.

[0037] Paramylon may be a single type or a combination of two or more types.

[0038] 3. Method for producing Euglena and paramylon Euglena can be prepared in large quantities by a method that includes a step of culturing Euglena contained in a liquid (culturing step). The culturing step can be carried out, for example, according to a known method (for example, the method described in Japanese Patent Publication No. 5883532). In this culturing step, Euglena microalgae are typically cultivated under aerobic conditions while stirring a liquid (culture medium) containing water, Euglena, and nutrients that Euglena can utilize.

[0039] Nutrients include sugars (monosaccharides such as glucose and fructose), minerals (e.g., sodium, potassium, magnesium, calcium, iron, zinc, molybdenum, copper, phosphorus, nitrogen, sulfur, or boron), and B vitamins (e.g., vitamin B1 (thiamine), vitamin B2 (riboflavin), niacin, pantothenic acid, vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine), vitamin B12 (cyanocobalamin), folic acid, biotin, etc.). The concentration of nutrients in the culture medium is not particularly limited as long as it is at a concentration that allows Euglena to survive and grow.

[0040] The light conditions for the cultivation process are not particularly limited, and the cultivation process may be carried out under either light or dark conditions. When culturing using heterotrophic methods, cultivation is performed under dark conditions. For light conditions, a normal light intensity for algal growth can be used. For dark conditions, for example, 10 μmol / m² 2 Conditions less than / s, preferably complete darkness where no light is present at all, are mentioned.

[0041] The culture temperature in the cultivation process is not particularly limited, as long as it is a temperature at which Euglena can grow. For example, a culture temperature (temperature of the culture medium) of 20°C to 35°C is used.

[0042] The pH of the liquid used in the culture process is not particularly limited, as long as it is within the range at which Euglena can grow. For example, a pH of 3.0 to 5.5 is used for Euglena growth.

[0043] After the culture process, it is preferable to concentrate the Euglena by methods such as centrifugation of the liquid or gravity separation. The obtained Euglena can be subjected to additional processing (e.g., suspension in liquid, dispersion in water or oil, extract, drying and powdering, etc.) depending on the desired form.

[0044] Paramylon particles can be produced by separating, isolating, or purifying them from Euglena according to known methods (e.g., the method described in Japanese Patent Publication No. 5883532). Paramylon particles can be easily obtained, for example, by recovering cellular contents obtained by disrupting the cell membrane of Euglena. Paramylon particles may also be purified as needed. Various methods for purifying paramylon particles are known (e.g., Japanese Patent Publication No. 5883532), and can be carried out according to these methods. Examples of purification steps include surfactant treatment and washing. The obtained Euglena can be subjected to additional processing (e.g., suspension in liquid, dispersion in water or oil, drying and powdering, etc.) depending on the desired form.

[0045] 4. Paramylon processed products Paramylon processed products are obtained by processing paramylon, such as physical treatment or chemical treatment, and are not particularly limited to that extent. Examples of paramylon processed products include fibrous paramylon and amorphous paramylon. Amorphous paramylon can be obtained by chemical treatment according to or similar to known methods, for example, using the method described in Japanese Patent Application Publication No. 2011-184592.

[0046] As the paramylon processed product, fibrous paramylon is preferred. Fiberus paramylon will be described below.

[0047] Fibrous paramylon is a β-1,3-glucan derived from Euglena, and is not particularly limited as long as it is in a fibrous form. Amorphous paramylon obtained by chemically treating paramylon particles (such as alkali treatment) has been reported, but when observed with an electron microscope, it is not recognized as fibrous and is an irregularly shaped mass, so it is not included in fibrous paramylon.

[0048] The weight-average molecular weight of fibrous paramylon is not particularly limited, but for example, 1 × 10⁻⁶ 4 ~2×107 Preferably 1 × 10 5 ~5×10 5 That is the case.

[0049] The weight-average molecular weight can be measured by SEC-MALS analysis using the following method: Detector: Multi-angle scattering detector (DAWN HELEOS II, Wyatt Technology) Differential refractometer detector (Optilab T-rEX, Wyatt Technology) Column: Two TSKgel α-M columns (Tosoh Corporation) Mobile phase: 0.05M potassium bromide-added DMSO Flow rate: 0.5 mL / min.

[0050] The fiber diameter of fibrous paramylon is not particularly limited, but is, for example, 10 to 500 nm, preferably 20 to 300 nm, and more preferably 50 to 200 nm. The fiber diameter of fibrous paramylon can usually be measured based on electron microscope images of the fibrous paramylon.

[0051] The volume of fibrous paramylon to be deposited in water is not particularly limited, but is, for example, 30 to 300 mL / g, preferably 50 to 250 mL / g, and more preferably 70 to 200 mL / g.

[0052] The volume of sediment in water can be measured according to or in accordance with the following method: The measurement will be performed in accordance with the method described in "Dietary Fiber - Fundamentals and Applications - 3rd Edition, p.111, Daiichi Shuppan, Tokyo (supervised by the Japanese Society for Dietary Fiber Research, edited by the Editorial Committee of the Japanese Society for Dietary Fiber Research, 2008)". Specifically, it will be as follows: Weigh 125 mg of the sample slurry into a 25 mL plastic tube (based on dry mass), and shake the plastic tube vigorously by hand to mix the contents. Then, transfer the contents to a 25 mL graduated cylinder and add pure water until the volume reaches 25 mL. After stirring the liquid in the graduated cylinder, let it stand at 37°C for 24 hours. This will cause the sample to precipitate, creating two layers separated by an interface (a layer mainly containing the precipitated sample (lower layer) and a layer mainly containing water (upper layer)). Determine the volume of the lower layer from the scale on the graduated cylinder, and divide the obtained volume by the sample mass (dry mass) to calculate the volume of sediment in water (mL / g). The test will be performed 3 or 4 times, and the mean and standard deviation will be calculated.

[0053] Fibrous paramylon exhibits relatively high resistance to enzymatic degradation. For example, the amount of monomer (glucose) produced by β-glucanase degradation is, for example, 0.1 to 50 mg, preferably 1 to 10 mg, per gram of fibrillated paramylon.

[0054] This quantity can be measured according to or in accordance with the following method: Prepare a reaction solution [30 mg of test substance (dry weight), 5 mL of buffer solution (Tokyo Chemical Industries, Ltd., B0156, potassium bitopropyl phthalate-sodium hydroxide buffer (pH 4.0)), 0.1 mL of enzyme solution (Nippon Biocon Co., Ltd., endo-1,3-β-Glucanase (enzyme content: 50 units / mL)), pure water, 10 mL of reaction solution] and shake horizontally at 45 rpm at 40°C for 24 hours. Immediately after shaking, freeze and store, then freeze-dry for concentration. After freeze-drying, add 0.5 mL of pure water to each sample and stir (20-fold concentration). Repeat the centrifugation (10000G, 5 minutes, 4°C) and collection of the supernatant twice. Measure the glucose concentration in the collected supernatant using a measurement kit (Wako Pure Chemical Industries, Ltd., Glucose CII-Test Wako). Calculate the amount of glucose produced per 1 g of test substance (mg) based on the measurement value.

[0055] Fiberized paramylon has relatively low solubility in alkaline solutions. For example, fiberized paramylon does not dissolve in a 0.1-0.3 M aqueous sodium hydroxide solution. Here, "does not dissolve" means, for example, that the absorbance (660 nm) of the solution after suspending fiberized paramylon in the aqueous solution (for example, immediately after to 1 hour later) is, for example, 0.1 or higher, preferably 1.0 or higher.

[0056] Solubility can be measured according to or in accordance with the following method: 250 mg (dry weight) of the test substance is suspended in 10 mL of the test solution (pure water, 0.1 M NaOH aqueous solution, 0.3 M NaOH aqueous solution) in a vial. The vial is shaken vigorously by hand for 20 seconds, and then shaken in a shaker at 80 rpm for 1 hour. The absorbance of the solution in the vial at 660 nm is measured after each shake. The absorbance is measured using a spectrophotometer V-730 manufactured by JASCO Corporation.

[0057] The relative value of the crystallinity of fibrous paramylon to granular paramylon (crystallinity of fibrous paramylon / crystallinity of granular paramylon) is, for example, 0.60 to 0.90, preferably 0.65 to 0.80.

[0058] Crystallinity can be measured according to or in accordance with the following method: XRD measurements will be performed on the test substance. The conditions are as follows: Instrument: PANalytical X'Pert3 Powder, Tube voltage: 45kV, Tube current: 40mA, Measurement range: 5.005~50.018°, Measurement interval: 0.013°, Analysis software: HighScore. Crystallinity will be analyzed by the ratio of the intensity of the amorphous region to the intensity of the crystalline region at 2θ=5~80°. The analysis will be performed after removing the instrument's background from each measurement test (background setting Auto, venting factor 0, granularity 100), and the amorphous region will be determined by the tangent passing through 2θ=14, 29°. The conditions for the pending factor and granularity used to determine each amorphous region will be 0 / 20.

[0059] Fiberized paramylon may be dispersed in a solvent such as water, or it may be in a dry form. Even in its dry form, fiberized paramylon can be redispersed in water.

[0060] In this specification, "dried form" means that the moisture content is 15% by mass or less, preferably 10% by mass or less, and more preferably 5% by mass or less.

[0061] Preferably, as the fibrous paramylon, a defibrated product of paramylon particles obtained by physically defibrating the paramylon particles can be used. Alternatively, a defibrated product of Euglena obtained by applying this defibration treatment to Euglena can also be used as the fibrous paramylon.

[0062] The defibration treatment is not particularly limited as long as it is a treatment that can defibrate the paramylon particles without breaking most of the hydrogen bonds of the β-1,3-glucan present in the paramylon particles (for example, by breaking only 10% or less, 5% or less, 2% or less, or 1% or less of the hydrogen bonds of the β-1,3-glucan), or a treatment that can unravel some or all of the β-1,3-glucan chains present in the paramylon particles or the triple helix structure they form. Preferably, the defibration treatment is performed without breaking most of the hydrogen bonds of the β-1,3-glucan present in the paramylon particles to make them fibrous. Known treatments that can grind (shear) or crush (preferably grind (shear)) fine particles such as paramylon particles can be used as the defibration treatment.

[0063] The defibration process can be carried out using known devices such as grinders (shearers) and crushers. Examples of devices used for the defibration process include millstone grinders, jet mills, twin-screw kneaders, high-pressure homogenizers, high-pressure emulsifiers, twin-screw extruders, and bead mills. Among these, millstone grinders and bead mills are preferred.

[0064] The defibration process can be carried out wet or dry. Wet defibration is preferable because it allows for more efficient dispersion of fibrous paramylon in the solution. When using a wet method, the solvent is not particularly limited as long as it can disperse fibrous paramylon; water is a suitable choice.

[0065] The defibration treatment may be performed by a single method or by a combination of two or more methods. Furthermore, the paramylon may be partially defibrated, and as long as it contains defibrated paramylon, it is in line with the intent of the present invention.

[0066] 5.Applications At least one substance selected from the group consisting of Euglena, paramylon, paramylon processed products, and β-1,3-glucan (hereinafter sometimes referred to as "the active ingredient of the present invention") has an antigen response enhancing effect and can therefore be used as an active ingredient in an antigen response enhancer.

[0067] Enhancement of antigen responsiveness refers to the enhancement of the reaction between antigen-presenting cells and T cells, particularly the enhancement of the reaction between antigen-presenting cells and naive T cells, and is not particularly limited to that extent. Enhancement of antigen responsiveness does not include T cell activation itself, or activation of T cells by the active ingredient of the present invention (i.e., it is enhancement of responsiveness to antigens other than the active ingredient of the present invention).

[0068] Enhanced antigen responsiveness can include, for example, promoting increased expression of molecules responsible for antigen presentation, promoting an increase in cells expressing molecules responsible for antigen presentation, promoting an increase in cells with high reactivity in antigen presentation, and promoting a decrease in cells with low reactivity in antigen presentation. More specifically, enhanced antigen responsiveness can be at least one selected from the group consisting of promoting an increase in CD28-positive CD57-negative T cells, promoting an increase in naive T cells, promoting increased CD28 expression in naive T cells, promoting increased CD80 expression in monocytes, promoting increased CD86 expression in monocytes, promoting increased HLA-DR expression in monocytes, promoting a decrease in CD28-negative CD57-positive T cells, promoting a decrease in terminally differentiated T cells, and promoting increased CD38 expression in monocytes. Positivity and negativity can be determined by staining with an antibody against the surface protein and then performing FACS analysis, mass cytometry, etc.

[0069] Furthermore, at least one selected from the group consisting of promoting the increase of CD28-positive CD57-negative T cells, promoting the increase of naive T cells, promoting the decrease of CD28-negative CD57-positive T cells, and promoting the decrease of terminally differentiated T cells has been reported as an indicator of immunosenescence. For this reason, the active ingredient of the present invention can also be used as an active ingredient in an immunosenescence inhibitor.

[0070] The active ingredient of the present invention can promote downstream immune activation of the antigen response. For example, the active ingredient of the present invention is useful for promoting increased CD38 expression in T cells, increased interleukin-17A, increased interleukin-17C, and increased granulocyte-macrophage colony-stimulating factor.

[0071] The active ingredient of the present invention can increase regulatory T cells. This makes it possible to suppress excessive inflammation while enhancing antigen responsiveness, thereby mitigating the adverse effects and diseases caused by it.

[0072] The active ingredient of the present invention is In addition to enhanced antigen response, It can be used in at least one selected from the group consisting of promoting the increase of CD28-positive CD57-negative T cells, promoting the increase of naive T cells, promoting the increase of CD28 expression in naive T cells, promoting the increase of CD80 expression in monocytes, promoting the increase of CD86 expression in monocytes, promoting the increase of HLA-DR expression in monocytes, promoting the decrease of CD28-negative CD57-positive T cells, promoting the decrease of terminally differentiated T cells, promoting the increase of CD38 expression in monocytes, promoting the increase of CD38 expression in T cells, promoting the increase of regulatory T cells, promoting the increase of interleukin-17A, promoting the increase of interleukin-17C, and promoting the increase of granulocyte-macrophage colony-stimulating factor.

[0073] "Enhancement" encompasses not only strengthening an effect, but also suppressing weakening of an effect that is on a weakening trend (reducing the degree or extent of weakening, or preventing weakening altogether).

[0074] "Promoting increase" encompasses not only increasing something, but also curbing a decline in something that is on a downward trend (reducing the rate or degree of decline, or preventing a decline altogether).

[0075] "Promoting a decrease" encompasses not only reducing something, but also curbing an increase in something that is on an upward trend (reducing the rate or extent of the increase, or preventing it from increasing at all).

[0076] Furthermore, the active ingredients of the present invention can be used for the following uses, purposes, and targets: (a) Maintain and enhance immune function. (b) Maintain or enhance antigen responsiveness. (c) Maintain or enhance antigen presentation ability. (d) Maintain and strengthen the coordination of co-stimulatory molecules. (e) To activate acquired immunity or put it into an activated state. (f) To activate, maintain, or enhance the active state of acquired immunity. (g) Maintain and enhance adaptive immune response. (h)Activates T cells. (i) To activate, maintain, or enhance the activity state of T cells. (j) Improves and suppresses T cell unresponsiveness. (k) Activates monocytes; puts them into an activated state. (l) Maintain and enhance the activity and activity state of monocytes. (m) Improves and suppresses immune aging. (n) Improves and suppresses the aging of T cells. (o) Maintain or improve your physical condition. (p) Increase and maintain naive cells. (q) Increase and maintain young T cells. (r) Increase and maintain healthy T cells. (s) Reduces and suppresses the increase of aged T cells.

[0077] The agent of the present invention can be used in various fields, for example, as a food composition (including health foods, health enhancers, and nutritional supplements), a food additive, a cosmetic, a cosmetic additive, a pharmaceutical, a reagent, or a feed. The agent of the present invention is preferably an oral composition.

[0078] The form of the agent of the present invention is not particularly limited and can take the form that is commonly used in each application, depending on the application.

[0079] Examples of the present invention's form of the agent when used in food compositions include liquid, gel, or solid foods such as juices, soft drinks, teas, soups, soy milk, salad oils, dressings, yogurts, jellies, puddings, furikake (rice seasonings), infant formula, cake mixes, dairy products (e.g., in powder, liquid, gel, or solid form), bread, and confectionery (e.g., cookies).

[0080] Examples of the present invention's formulations, when used in cosmetics, include emulsions, cosmetic liquids, face creams, hand creams, lotions, body soaps, shampoos, conditioners, cosmetic gels, masks, foundations, lip balms, and facial cleansers.

[0081] The forms of the preparation of the present invention include, when the use is pharmaceutical, preparations suitable for parenteral administration (especially external preparations), such as ointments, external liquids (liniments, lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, patches (plasters, ointments, tapes (reservoir type, matrix type, etc.), poultices, patches, microneedles, etc.), eye drops, eye ointments, nasal drops, suppositories, semi-solid rectal preparations, and enema preparations; and preparations suitable for oral administration (oral preparations), such as tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, jelly-like drops, etc.), pills, granules, fine granules, powders, hard capsules, soft capsules, dry syrups, liquids (including drinks, suspensions, syrups), and jellies.

[0082] Examples of the present invention's formulations, when used as additives, health enhancers, or nutritional supplements, include tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, and jelly-like drops), pills, granules, fine granules, powders, hard capsules, soft capsules, dry syrups, liquids (including suspensions and syrups), and jellies.

[0083] The agent of the present invention may further contain other components as needed. Other components are not particularly limited as long as they can be incorporated into food compositions (including health foods, health enhancers, nutritional supplements), food additives, cosmetics, cosmetic additives, pharmaceuticals, reagents, animal feed, etc., but examples include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, colorants, fragrances, chelating agents, and the like.

[0084] The content of the active ingredient in the agent of the present invention depends on the application, manner of use, and the condition of the target, and is not limited, but can be, for example, 0.0001 to 100% by mass, preferably 0.001 to 50% by mass.

[0085] The amount of the agent of the present invention to be administered (e.g., given, ingested, or inoculated) is not particularly limited as long as it is an effective amount that exhibits an antigen-response-enhancing effect, and is generally 0.1 to 10,000 mg / kg body weight per day as the dry weight of the active ingredient. The above amount is preferably administered in one or more divided doses per day (e.g., 1 to 3 times), and can be increased or decreased as appropriate depending on age, condition, and symptoms.

[0086] In a preferred embodiment of the present invention, the amount of Euglena applied (dry weight) is preferably 50 to 3000 mg per day, more preferably 100 to 2000 mg, and even more preferably 200 to 1000 mg. The application period is preferably 1 week or more, more preferably 4 weeks or more, and even more preferably 8 weeks or more. It is also possible to apply it for an even longer period (10 weeks or more, 15 weeks or more, or 20 weeks or more). Since the active ingredient of the present invention is naturally derived and highly safe, there is no particular upper limit to the application period, but examples include 3 years, 1 year, 6 months, and 4 months. [Examples]

[0087] The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[0088] Manufacturing Example 1 Euglena gracilis EOD-1 strain (dried powder from the National Institute of Technology and Evaluation Patent Organism Depository Center (NITE-IPOD) manufactured by Kobe Steel Environmental Solutions, with a paramylon content of 70% or more) was used as the test food in the following formulation (capsule components: pullulan and sorghum pigment), and capsule tablets containing cellulose (capsule components: pullulan and sorghum pigment) were manufactured as a control food.

[0089] [Table 1]

[0090] Content of each ingredient (daily intake) Test Example 1 The exam details are as follows: • Test diet intake period: 12 weeks • Dosage of test food: 2 capsules / day • Subjects: 12 people on the test diet, 11 people on the control diet.

[0091] The test diet consisted of two types: a test food and a control food (placebo) (Manufacturing Example 1). The test food was a food containing Euglena gracilis EOD-1 strain, and the control food (placebo) was a food not containing Euglena gracilis EOD-1 strain.

[0092] The test diet was administered as two capsules per day for 12 weeks. The total amount of ingredients in each capsule was as follows: Test diet: Contains 444 mg of Euglena gracilis EOD-1 strain (350 mg as paramylon). Control diet: Contains 350 mg of cellulose.

[0093] At the start and end of the study (12 weeks after the start of intake), blood was collected from each subject using heparinized blood collection tubes and heparinized whole blood. Peripheral blood mononuclear cells (PBMCs) were isolated from the blood by centrifugation.

[0094] <Test Example 1-1. Antigen Response Evaluation 1> PBMCs isolated using the Maxpar Direct Immune Profiling Assay kit (Fluidime) were stained. Mass cytometry was used to measure the proportion of CD28+CD57- cells, CD28-CD57+ cells, naive cells, and terminally differentiated cells among CD4+ T cells and CD8+ T cells. The staining antibodies used for gating each cell type were: 89Y Anti-CD45 (HI30), 172Yb Anti-CD66b (G10F5), 144Nd Anti-CD19 (HIB19), 171Yb Anti-CD20 (2H7), 168Er Anti-CD14 (63D3), 147Sm Anti-CD11c (Bu15), 170Er Anti-CD3 (UCHT1), 164Dy Anti-TCRγδ(B1), 163Dy Anti-CD56 (NCAM16.2), 146Nd Anti-CD8a (RPA-T8), 145Nd Anti-CD4 (RPA-T4), 160Gd Anti-CD28 (CD28.2), 155Gd Anti-CD57 (HCD57), and 176Yb Anti-CD127. The drugs used were (A019D5), 153Eu Anti-CD25 (BC96), 167Er Anti-CCR7 (G043H7), and 150Nd Anti-CD45RA (HI100). Mass cytometry was performed using Helios (Fluidime). Data analysis was performed using Flow Jo software (BD). The change (%) was calculated by subtracting the average percentage of CD28+CD57- cells, CD28-CD57- cells, naive cells, and terminally differentiated cells in CD4+ T cells and CD8+ T cells after 12 weeks of intake from the average percentage of CD28+CD57- cells, CD28-CD57- cells, naive cells, and terminally differentiated cells in CD4+ T cells and CD8+ T cells before the start of intake of the test food.In the following items, "+" indicates a positive result and "-" indicates a negative result. CD4+ T cells are defined as cells that are gated to CD45+ / CD66b-, CD20- / CD19-, CD14- / CD11c-, CD45+ / CD3+, TCRgd- / CD3+, CD56- / CD3+, CD8- / CD4+, and CD8+ T cells are defined as cells that are gated to CD45+ / CD66b-, CD20- / CD19-, CD14- / CD11c-, CD45+ / CD3+, TCRgd- / CD3+, CD56- / CD3+, CD8+ / CD4-. (1) Percentage of CD28+CD57-CD4+ T cells (2) Percentage of CD28+CD57-CD8+ T cells (3) Percentage of naive type (CD45RA+ / CCR7+, CD127+ / CD25-) CD4+ T cells (4) Percentage of terminally differentiated (CD45RA+ / CCR7-) CD4+ T cells (5) Percentage of CD28-CD57+ CD4+ T cells (6) Percentage of CD28-CD57+ CD8+ T cells (7) Percentage of naive (CD45RA+ / CCR7+) CD8+ T cells (8) Percentage of terminally differentiated (CD45RA+ / CCR7-) CD8+ T cells The CD28+CD57- T cells in items (1) and (2) are negative for CD57, a molecule expressed in the late stages of differentiation, and are T cells that have not undergone senescence. On the other hand, the CD28-CD57+ T cells in items (5) and (6) are positive for CD57, a molecule expressed in the late stages of differentiation, and are senescent T cells. Senescent T cells have lost their ability to proliferate after antigen stimulation.

[0095] Naive T cells, described in items (3) and (7), are T cells that have never come into contact with an antigen and exhibit excellent responsiveness and proliferation to new antigens. On the other hand, terminally differentiated T cells (TEMRA), described in items (4) and (8), are cells that increase with age and have lost their ability to proliferate after antigen stimulation.

[0096] The results for (1) to (4) are shown in Figures 1 to 4. It was found that Euglena intake promoted the increase of non-aging cells / naive T cells ((1) to (3)), while Euglena intake promoted the decrease of senescent cells ((4)). Similarly, for (5) to (8), Euglena intake promoted the increase of non-aging cells / naive T cells ((7)), while Euglena intake promoted the decrease of senescent cells ((5) to (6) and (8)). It was speculated that these results were due to paramylon contained in Euglena.

[0097] <Test Example 1-2. Antigen Response Evaluation 2> PBMCs isolated using the Maxpar Direct Immune Profiling Assay kit (Fluidigm) were stained. CD28 expression levels in naive CD4+ T cells and CD8+ T cells were measured by mass cytometry. The antibodies used to stain each cell were: 89Y Anti-CD45 (HI30), 172Yb Anti-CD66b (G10F5), 144Nd Anti-CD19 (HIB19), 171Yb Anti-CD20 (2H7), 168Er Anti-CD14 (63D3), 147Sm Anti-CD11c (Bu15), 170Er Anti-CD3 (UCHT1), 164Dy Anti-TCRγδ(B1), 163Dy Anti-CD56 (NCAM16.2), 146Nd Anti-CD8a (RPA-T8), 145Nd Anti-CD4 (RPA-T4), 160Gd Anti-CD28 (CD28.2), 176Yb Anti-CD127 (A019D5), and 153Eu Anti-CD25. The antibodies tested were (BC96), 167Er Anti-CCR7 (G043H7), and 150Nd Anti-CD45RA (HI100). Mass cytometry was performed using Helios (Fluidigm). Data analysis was performed using Flow Jo software (BD). In the following items, "+" indicates a positive result and "-" indicates a negative result. (9) CD28 expression level in naive CD4+ T cells (10) CD28 expression level in naive CD8+ T cells CD28 is an essential co-stimulatory receptor for T cell activation. Therefore, higher CD28 expression levels in naive T cells indicate higher antigen responsiveness.

[0098] The results are shown in Figures 5-6. It was found that CD28 expression in naive T cells was increased and promoted by Euglena intake. It was hypothesized that this result was due to paramylon contained in Euglena.

[0099] <Test Example 1-3. Antigen Response Evaluation 3> Isolated PBMCs were stained with FITC Anti-Human CD14 (Bio Legend), APC Anti-Human CD16 (Bio Legend), Per Cp / Cyanine 5.5 Anti-Human HLA-DR (Bio Legend), PE Anti-Human CD80 (Bio Legend), and PE Anti-Human CD86 (Bio Legend). After washing with FACS buffer (0.5% BSA in PBS buffer), they were fixed with 4% paraformaldehyde and processed using BD FACS via TM Measurements were performed using a Flow Cytometer (BD Japan). BD FACS Via TM Using Research Software (BD Japan), the following parameters were measured using monocytes, which are CD14-positive / CD16-positive cells from an HLA-DR-positive cell population. (11) CD80 expression level in monocytes (12) CD86 expression level in monocytes (13) HLA-DR expression levels in monocytes CD80 and CD86 are molecules expressed on the surface of antigen-presenting cells that have been activated by taking up an antigen. They promote T cell activation by binding to CD28 on naive T cells. HLA-DR promotes T cell activation by forming a complex with the antigen and presenting it to naive T cells.

[0100] The results for (11) are shown in Figure 7. It was found that CD80 expression in monocytes was increased and promoted by Euglena intake. Furthermore, the results for (12) and (13) were also increased and promoted by Euglena intake. It was presumed that the above results were due to paramylon contained in Euglena.

[0101] <Test Example 1-4. Antigen Response Evaluation 4> PBMCs isolated using the Maxpar Direct Immune Profiling Assay kit (Fluidime) were stained. CD38 expression levels were measured by mass cytometry in naive CD4+ T cells, CD4+ central memory T cells (Tcm), CD4+ effector memory T cells (Tem), naive CD8+ T cells, terminally differentiated CD8+ T cells (Temra), intermediate monocytes, and nonclassical monocytes. The antibodies used to stain each cell were: 89Y Anti-CD45 (HI30), 172Yb Anti-CD66b (G10F5), 144Nd Anti-CD19 (HIB19), 171Yb Anti-CD20 (2H7), 168Er Anti-CD14 (63D3), 147Sm Anti-CD11c (Bu15), 170Er Anti-CD3 (UCHT1), 164Dy Anti-TCRγδ(B1), 163Dy Anti-CD56 (NCAM16.2), 146Nd Anti-CD8a (RPA-T8), 145Nd Anti-CD4 (RPA-T4), 176Yb Anti-CD127 (A019D5), 153Eu Anti-CD25 (BC96), and 167Er Anti-CCR7. The results were (G043H7), 150Nd Anti-CD45RA (HI100), 148Nd Anti-CD16 (3G8), and 161Dy Anti-CD38 (HB-7). Mass cytometry measurements were performed using Helios (Fluidime). Data analysis was performed using Flow Jo software (BD). In the following items, "+" indicates a positive result and "-" indicates a negative result. (14) CD38 expression level in naive CD4+ T cells (15) CD38 expression level in CD4+ central memory T cells (CD4+ T cells with Tcm:CD45RA- / CCR7+, CD25- / CD127+) (16) CD38 expression level in CD4+ effector memory T cells (CD4+ T cells with Temp:CD45RA- / CCR7-, CD25- / CD127+) (17) CD38 expression level in naive CD8+ T cells (18) CD38 expression level in terminally differentiated CD8+ T cells (19) CD38 expression levels in intermediate monocytes (CD45+ / CD66b-, CD3- / CD19-, CD20- / HLA-DR+, HLA-DR+ / CD11c, CD38int / CD14int, CD14+- / CD16+) (20) CD38 expression levels in nonclassical monocytes (CD45+ / CD66b-, CD3- / CD19-, CD20- / HLA-DR+, HLA-DR+ / CD11c, CD38- / CD14-, CD14+- / CD16+) Increased CD38 expression in T cells promotes activation, differentiation, and proliferation of effector T cells. Increased CD38 expression in antigen-presenting cells such as monocytes promotes migration to inflammatory and infection sites.

[0102] The results for (14) to (18) are shown in Figure 8, and the results for (19) to (20) are shown in Figure 9. It was found that CD38 expression levels in T cells and monocytes were increased and promoted by Euglena intake. It was presumed that these results were due to paramylon contained in Euglena.

[0103] <Test Example 1-5. Measurement of Regulatory T Cells> PBMCs isolated using the Maxpar Direct Immune Profiling Assay kit (Fluidigm) were stained. The proportion of regulatory T cells (Tregs) among CD4+ T cells was measured by mass cytometry. The staining antibodies used for cell gating were 89Y Anti-CD45 (HI30), 172Yb Anti-CD66b (G10F5), 144Nd Anti-CD19 (HIB19), 171Yb Anti-CD20 (2H7), 168Er Anti-CD14 (63D3), 147Sm Anti-CD11c (Bu15), 170Er Anti-CD3 (UCHT1), 164Dy Anti-TCRγδ(B1), 163Dy Anti-CD56 (NCAM16.2), 146Nd Anti-CD8a (RPA-T8), 145Nd Anti-CD4 (RPA-T4), 176Yb Anti-CD127 (A019D5), and 153Eu Anti-CD25 (BC96). (21) Percentage of regulatory T cells (CD25+ / CD127- CD4+ T cells) Regulatory T cells are known to be cells that suppress the immune response. Studies have shown that an increase in these cells can suppress excessive inflammation, thereby mitigating the adverse effects and diseases caused by excessive inflammation.

[0104] The results of (21) are shown in Figure 10. It was found that regulatory T cells were increased and promoted by Euglena intake. It was presumed that the above results were due to paramylon contained in Euglena.

[0105] <Test Example 1-6. Measurement of Cytokines> Serum was prepared from isolated blood samples, and the levels of interleukin-17A (IL17A), interleukin-17C (IL17C), and granulocyte-macrophage colony-stimulating factor (GM-CSF (CSF2)) in the serum were measured using the Proximity Extension Assay method. Whole blood samples were centrifuged at 1300 × g for 15 minutes at room temperature to obtain serum. The concentrations of each cytokine in the prepared serum were quantified using the Olink Target 48 Cytokine panel (Olink Holding, Sweden). (22) Amount of interleukin-17A in serum (23) Amount of interleukin-17C in serum (24) Amount of granulocyte-macrophage colony-stimulating factor in serum Interleukin-17A, interleukin-17C, and granulocyte-macrophage colony-stimulating factor are all molecules involved in T cell activation.

[0106] The results of (22) to (24) are shown in Figure 11. It was found that interleukin-17A, interleukin-17C, and granulocyte-macrophage colony-stimulating factor were increased and promoted by Euglena intake. It was presumed that the above results were due to paramylon contained in Euglena.

Claims

1. An antigen response enhancer containing Euglena gracilis, The antigen responsiveness enhancer is an agent used to administer 0.1 to 10,000 mg / kg body weight of Euglena gracilis per day as dry weight, and The antigen response enhancer is an agent used to enhance antigen response using at least one indicator selected from the group consisting of promoting the increase of CD28-positive CD57-negative T cells, promoting the increase of naive T cells, promoting the increase of CD28 expression in naive T cells, promoting the increase of CD80 expression in monocytes, promoting the increase of CD86 expression in monocytes, promoting the increase of HLA-DR expression in monocytes, promoting the decrease of CD28-negative CD57-positive T cells, promoting the decrease of terminally differentiated T cells, and promoting the increase of CD38 expression in monocytes.

2. The antigen response enhancer according to claim 1, wherein the Euglena gracilis is Euglena gracilis EOD-1 strain (accession number FERM BP-11530).

3. The antigen responsiveness enhancer according to claim 1 or 2, wherein the antigen responsiveness enhancer is further an agent for use in suppressing immunosenescence.

4. The antigen responsiveness enhancer according to claim 1 or 2, wherein the antigen responsiveness enhancer is further an agent for use in at least one selected from the group consisting of promoting increased CD38 expression in T cells, promoting increased regulatory T cells, promoting increased interleukin-17C, and promoting increased granulocyte-macrophage colony-stimulating factor.

5. An antigen responsiveness enhancer according to claim 1 or 2, which is a food composition, nutritional supplement, food additive, or pharmaceutical product for use in enhancing antigen responsiveness using at least one indicator selected from the group consisting of promoting the increase of CD28-positive CD57-negative T cells, promoting the increase of naive T cells, promoting the increase of CD28 expression in naive T cells, promoting the increase of CD80 expression in monocytes, promoting the increase of CD86 expression in monocytes, promoting the increase of HLA-DR expression in monocytes, promoting the decrease of CD28-negative CD57-positive T cells, promoting the decrease of terminally differentiated T cells, and promoting the increase of CD38 expression in monocytes.

6. An antigen responsiveness enhancer according to claim 1 or 2, which is an oral composition for use in enhancing antigen responsiveness using at least one selected from the group consisting of promoting the increase of CD28-positive CD57-negative T cells, promoting the increase of naive T cells, promoting the increase of CD28 expression in naive T cells, promoting the increase of CD80 expression in monocytes, promoting the increase of CD86 expression in monocytes, promoting the increase of HLA-DR expression in monocytes, promoting the decrease of CD28-negative CD57-positive T cells, promoting the decrease of terminally differentiated T cells, and promoting the increase of CD38 expression in monocytes as an indicator.

7. An immunosenescence inhibitor containing Euglena gracilis, The immunosenescence inhibitor is a preparation for use in which the dry weight of Euglena gracilis is ingested at a rate of 0.1 to 10,000 mg / kg body weight per day, and The immunosenescence inhibitor is an agent used for suppressing immunosenescence using at least one indicator selected from the group consisting of promoting the increase of CD28-positive CD57-negative T cells, promoting the increase of naive T cells, promoting the decrease of CD28-negative CD57-positive T cells, and promoting the decrease of terminally differentiated T cells.

8. Contains Euglena gracilis, This is for the purpose of using the aforementioned Euglena gracilis in a dry weight of 0.1 to 10,000 mg / kg body weight per day, and For use in at least one selected from the group consisting of promoting the increase of CD28-positive CD57-negative T cells, promoting the increase of naive T cells, promoting increased CD28 expression in naive T cells, promoting increased CD80 expression in monocytes, promoting increased CD86 expression in monocytes, promoting increased HLA-DR expression in monocytes, promoting the decrease of CD28-negative CD57-positive T cells, promoting the decrease of terminally differentiated T cells, promoting increased CD38 expression in monocytes, and promoting increased CD38 expression in T cells, composition.

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