TW201416084A - Immunemodulating agent - Google Patents

Abstract

Provided is an immunomodulating agent for modulating abnormal immunity, particularly an excess immune response. The present inventors have made extensive studies. As a result, it is found that a mangosteen peel extract produced by extracting a mangosteen peel with a polar solvent has a function of modulating immunity, and the mangosteen peel extract is provided as an immunomodulating agent.

Description

Immunomodulator

The present invention relates to immunomodulators.

Higher animals have foreign bodies in bacteria, viruses, poisons, etc. Defend the body's immune function during the invasion. If the immune function is lowered, it is easy to cause an infection caused by bacteria or the like. On the other hand, if the immune function is excessive, it will cause diseases called allergies and autoimmune diseases. The present invention aims to provide an immunomodulator capable of preventing, treating or alleviating a disease caused by an immune abnormality, particularly an excessively active immune function.

The immune response is T cells, B cells, dendritic cells, giant Cells such as phagocytes and mast cells participate. According to surface antigens, T cells can be divided into helper T cells and killer T cells, and helper T cells can be further divided into Th1 cells and Th2 cells according to the state of secreted interleukins. The dominant immune response of Th1 cells induces cellular immunity called Th1-type response, and the dominant immune response of Th2 cells induces humoral immunity called Th2-type response. The Th1-type immune response and the Th2-type immune response maintain a balance in the normal state, which can cause disease if it is heavily biased to either side, that is, if the Th1 type immune response is hyperactive, it will induce autoimmunity. Epidemic disease; if the Th2 type of immune response is hyperactive, it will induce allergies.

Infected by viruses and parasites, it promotes Th0 cells. Differentiation into Th1 cells and activation of cellular immunity. Th1 cells produce interleukins such as interferon gamma (IFN-γ) and interleukin (IL)-2, activate T cells, macrophages, etc., and attack virus-infected cells. When the Th1 type immune response is hyperactive, autoreactive T cells are activated, and chronic inflammation and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and insulin-dependent diabetes mellitus are induced.

On the other hand, if environmental antigens such as cockroaches and room dust come from outside When the body invades the body, it induces the differentiation of Th0 cells into Th2 cells and activates humoral immunity.

The onset of allergies is associated with a Th2-type response. Room dust After the environmental antigen invades the living body, thoracic stromal lymphopoietin (TSLP: thymic stromal lymphopoietin) is produced from epidermal keratinocytes. TSLP activates dendritic cells and promotes the differentiation of Th0 cells into Th2 cells. Self-activated Th2 cells produce IL-4, IL-13, which act on B cells, produce antibodies specific for the antigen, and induce humoral immunity. At this time, there are cases where IgE antibodies are largely induced due to certain mechanisms. When IgE binds to FcεRI on mast cells and basophilic spheres and cross-links with re-invading antigens, it promotes aggregation of FcεRI and initiates activation of mast cells and basophils. At this time, chemical substances such as histamine, neutral protease, and proteoglycan accumulated in the cytoplasmic granules are released and cause an allergic reaction. Further, there are cases in which an acidophilic ball caused by IL-5 produced from Th2 cells is induced. Infiltration into the lesion, and infiltration of Th2 cells into the lesion caused by chemokine called CCL22 and CCL24 produced by activated dendritic cells, causing an allergic reaction to inflammation.

In recent years, allergies have been thought to be associated with a lack of skin barriers. It also has a relationship. The skin is composed of four layers: epidermis, basement membrane, dermis and subcutaneous tissue. The epidermis is classified into stratum corneum, granular layer, spinous layer and basal layer. The cell barrier is formed by regular cell proliferation and differentiation of keratinocytes occupying most of the epidermal cell layer, preventing water dispersion in the stratum corneum from being lost to the outside, and also invading the body from environmental antigens such as room dust from the outside. Skin diseases such as dry phlegm, actinic keratosis, ichthyosis, and liposuction dermatitis have a flaw in cell proliferation control of keratinocytes, causing abnormal proliferation of skin epithelial cells and causing hypertrophy of the skin. As a result, environmental antigens become more susceptible to invasion due to a decrease in barrier function of the epidermis.

Aquaporin 3 (AQP3: Aquaporin 3) has been reported As a factor controlling the proliferation of keratinocyte cells. AQP3 has been reported as a transport protein of water and glycerol present on the surface of cell membranes, which is responsible for controlling cell proliferation, movement and water transport, and is associated with physiological moisturization and wound healing of the skin. In addition, keratinocytes release inflammatory interleukins and chemokines such as IL-1, IL-6, TNF-α, TSLP, and CCL-17 by various stimuli, and activate immune cells such as immune cells. China also plays an important role. Furthermore, keratinocytes have been reported to release NGF (Nerve growth factor) by various stimuli, causing an increase in peripheral nerves, hypertrophy, and enhanced sensitivity to external stimuli. When the susceptibility to stimulation increases, it will cause scratching. In this case, the epidermal barrier is Destruction, the production of inflammatory interleukins is induced and becomes a vicious circle with a more aggressive immune response.

For the prevention and treatment of immune diseases, look forward to finding out A substance that can control immune function and epidermal barrier function, that is, it can inhibit Th1/Th2 interleukin and IgE production, and can also control abnormal proliferation of keratinocytes, inflammatory interleukins derived from keratinocytes or substances produced by NGF. Substance.

In this context, the development of immunomodulatory substances Exploration, rice raw material brewing (Patent Document 1), acetic acid, and propionic acid (Patent Document 2) and the like have been disclosed. However, each of these substances has only the effect of balancing Th1/Th2, and it has not been revealed that it also has a multifaceted effect including an improvement of the epidermal barrier.

In order to solve the problems of the prior art as described above, the present invention It is an immunomodulator that is safe from the mangosteen peel extract and has an effect of regulating immune abnormalities.

Mangosteen (Garcinia mangostana. used in the present invention. Lnn) belongs to the genus Garcinia. Mangosteen is an edible fruit tree that grows in Southeast Asia. Its peel has been used as a folk heritage medicine since the ancient times for diarrhea, red peony, antipyretic and skin diseases. Mangosteen is known as the queen of fruits and is a well-known and well-known material. Therefore, the immunomodulator formed by the mangosteen peel extract is better and can be more easily accepted by patients.

About the effectiveness of mangosteen, it is known to be purified from mangosteen extract The α-mangosteen flavonoids and γ-mangosteen flavonoids have anti-histamine effects or anti-serotonin effects, and α-mangosteen flavonoids and γ-mangosteen flavonoids also show to humans. Inhibition effect of hay fever (Patent Document 3). Further, it is also known that mangosteen extract, in particular, α-mangosteen flavonoids and γ-mangosteen flavonoids have an inhibitory effect on IκB kinase (Patent Document 4). Further, it is also known that mangosteen extract has an effect of preventing/treating atopic dermatitis (Patent Document 5).

Further, Non-Patent Document 1 discloses that γ-mangosteen flavonoids can be inhibited The activity of Iκ kinase inhibits the release of prostaglandin E, which inhibits the expression of the cyclooxygenase 2 gene. Non-Patent Document 2 discloses that IMD-0354, an IκB kinase activity inhibitor, has an effect of treating atopic dermatitis which is one of immune abnormalities at the animal level. Non-Patent Document 3 discloses that α-Mangosteen Flavonoid has an anti-proliferative effect on lymphocytic leukemia B cells. Non-Patent Document 4 discloses that α-mangosteen flavonoids and γ-mangosteen flavonoids have an anti-proliferative effect on human leukemia cell line HL60.

Non-Patent Document 5 discloses mangosteen peel extract on human knots The rectal adenocarcinoma cell line COLO205 has an anti-proliferative effect.

[Previous Technical Literature] [Patent Document]

[Patent Document 1] Japanese Special Open 2008-195713

[Patent Document 2] Japanese Special Open 2009-292785

[Patent Document 3] Japanese Patent No. 3968405

[Patent Document 4] Japanese Special Open 2010-195831

[Patent Document 5] Japan Re-Form 2009-142320

[Non-patent literature]

[Non-Patent Document 1] Mol. Pharmacol., 66, p667 (2004)

[Non-Patent Document 2] J Invest Dermatol., 127, P855 (2007)

[Non-Patent Document 3] Planta Med., 75, P243 (2009)

[Non-Patent Document 4] J Nat Prod., 66, P1124 (2003)

[Non-Patent Document 5] Appl Biotechnol., 162, P1080 (2010)

In order to regulate immune abnormalities, in particular, the provision of immunomodulators for regulating excess immune responses.

As a result of intensive research by the inventors, it was found that mangosteen peel extract extracted from mangosteen peel has the function of regulating immunity and provides this as an immunomodulator.

An immunomodulator composed of mangosteen peel extract inhibits cell proliferation and inhibits the production of IgE, IFN-γ, TSLP, IL-4, CCL22, CCL24, NGF, AQP3 and the like.

Mangosteen is highly edible since it has been eaten since ancient times.

[Fig. 1] A result of investigating the effect exhibited by mangosteen peel extract on cell proliferation.

[Fig. 2] The results of investigating the effects exhibited by mangosteen peel extract on IgE production.

[Fig. 3] The results of examining the effects exhibited by the mRNA layer mangosteen extract on the production of interleukins were investigated.

Fig. 4 is a graph showing the results of examining the effects of mangosteen peel extract on the production of interleukins at the mRNA level.

[Fig. 5] A result of investigating the effect exhibited by the mangosteen peel extract on the production of TSLP at the mRNA level.

[Fig. 6] A result of examining the effect exhibited by the mangosteen peel extract on the production of endogenous proteins such as interleukins and chemokines at the mRNA level.

The present invention provides an immunomodulator made from mangosteen peel extract. An immunomodulator made from mangosteen peel extract inhibits cell proliferation. Although the type of the cell is not limited, the cell may be exemplified by keratinocytes, mast cells, and B cells. Moreover, an immunomodulator composed of mangosteen peel extract inhibits the production of IFN-γ. Moreover, the immunomodulator produced by the mangosteen peel extract inhibits the production of TSLP. Further, the immunomodulator produced by the mangosteen peel extract inhibits the production of IL-4, CCL22 (MDC), CCL24 (Eotaxin-2), NGF, and AQP3.

In addition, the present invention provides a form of α-mangosteen flavonoids Immunomodulator. An immunomodulator composed of α-mangosteen inhibits cell proliferation and production of IgE, IFN-γ or TSLP.

In addition, the present invention provides a γ-mangosteen flavonoid Immunomodulator. An immunomodulator composed of γ-mangosteen inhibits cell proliferation and production of IgE or IFN-γ.

Furthermore, the present invention provides a food or drink for immunomodulation comprising any one of the above-described immunomodulators.

Mangosteen belongs to the genus Garcinia Cambogia. The mangosteen peel can be obtained from mangosteen fruit (raw or dried).

The so-called mangosteen peel extract refers to an extract extracted from mangosteen peel by a solvent. The solvent used for the extraction is not particularly limited, but a polar solvent is preferred. Preferable examples include a polar solvent selected from the group consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, acetone, ethyl acetate, and water, or a mixture thereof. Solvent. When it is considered to be used as an oral administration or food or drink, it is preferable to use ethanol as an extraction solvent or a combination of water and ethanol in terms of safety. Although the temperature of the extraction is not particularly specified, the range from room temperature to the boiling point of the solvent is suitable from the viewpoint of extraction efficiency. Although the extraction time varies depending on the type of solvent, the state of the peel (raw or dried product, pulverized material or powder, etc.) and the extraction temperature, it is suitable in the range of 0.5 to 24 hours.

The extract may be concentrated by an evaporator or the like as necessary, or may be removed. Further, the extract may be used after purification by a solvent partial separation method or a chromatography method if necessary.

The so-called immunomodulator refers to the regulation of immune response The agent, and more preferably in the present invention, refers to a modulator that inhibits an excessive immune response. Examples of the immunomodulation include inhibition of cell proliferation, antibodies, particularly preferably inhibition of IgE production, endogenous proteins related to so-called interleukins, and immunoreactions of chemokines, such as IFN-γ, TSLP, IL- 4. Inhibition of CCL22, CCL24, NGF, AQP3.

The α-mangosteen flavonoid has a compound of the following structure (1) and can be extracted from mangosteen peel.

The so-called γ-mangosteen flavonoids have the following structure of (2) The substance can be extracted from the mangosteen peel.

[Example 1] ‧ Preparation of mangosteen peel extract

100 g of the undried peel of mangosteen was pulverized, and further immersed in 1 L of a 70% ethanol solution for 1 hour, and the mixture was stirred and extracted at 80 °C. This was filtered, and the filtrate was dried under reduced pressure in an evaporator to give 27.4 g of an extract. This is used as a mangosteen peel extract. Hereinafter, in the present specification, this extract is sometimes referred to as ME70.

‧α-Mangosteen Flavonoids, Preparation of γ-Mangosteen Flavonoids

1 kg of undried peel of mangosteen was immersed in 10 L of ethanol and extracted at room temperature for 24 hours. After filtration, the filtrate was dried under reduced pressure with an evaporator to give 80 g of an extract. 80 g of the obtained extract was dissolved in 350 ml of ethyl acetate, and then washed twice with 200 ml of water. The ethyl acetate was partitioned and the solvent was distilled off by an evaporator to obtain 20 g of dried material. This dried product was purified by ceria gel column chromatography. The eluted solution was gradually eluted with a gradient of polarity by a hexane-ethyl acetate system, and three divided layers were obtained. The initially obtained partition layer (5g) was again purified by cerium oxide gel column chromatography (hexane-ethyl acetate, 10:90→30:70→50:50) to obtain 2g of α-mangosteen flavonoids. Yellow crystalline sample. The second dividing layer (2g) was again analyzed by cerium oxide gel column chromatography (hexane-ethyl acetate 30:70→50:50, followed by ethyl acetate only, and finally ethyl acetate-methanol) 50:50) Purification gave 500 mg of a yellow amorphous sample of γ-mangosteen flavonoids.

[Example 2] ‧ test method

The effects of mangosteen peel extract, α-mangosteen flavonoids, and γ-mangosteen flavonoids on the proliferation of keratinocytes, mast cells, and B cell cell lines were examined.

Mouse keratinocyte strain PAM212 was cultured in DMEM (Invitrogen, Carlsbad, USA, Cat. No. 12100-046) medium (containing 10% FCS, 100 U/ml P-S). The mouse mast cell line P815 was cultured in RPMI1640 medium (containing 10% FCS, 100 U/ml P-S). The mouse B cell line BCL1 was cultured in RPMI1640 medium (containing 10% FCS, 100 U/ml P-S).

Various concentrations of samples (mangosteen peel extract (ME70), α-mangosteen flavonoids, γ-mangosteen flavonoids, IMD-0354, FK506) were added to the suspension of each cell, and then seeded in a 96-well plate (100 μl/well). . Set the group to which no sample was added as a control group. FK506 is a well-known immunosuppressive agent.

Further, PAM212 was seeded at a concentration of 2 × 10 ⁴ cells/ml. P815 was sown at a concentration of 5 x 10 ⁴ cells/ml. BCL1 was sown at a concentration of 2 x 10 ⁵ cells/ml.

After 24, 48, and 72 hours of sowing, the number of viable cells was measured by trypan blue dye exclusion test.

‧result

The results are shown in Table 1 and Figure 1. Mangosteen peel extract, α-mangosteen flavone, and γ-mangosone flavone inhibited the proliferation of mouse keratinocyte cell line PAM212. The IC50 was 5.9 μg/ml, 3.8 μM, and 1.6 μM, respectively.

Mangosteen peel extract, α-mangosteen flavonoids and γ-mangosteen flavone inhibited the proliferation of mouse mast cell line P815. The IC50 was 7.7 μg/ml, 3.0 μM, and 3.1 μM, respectively.

Mangosteen peel extract, α-mangosteen flavone, and γ-mangosone flavone inhibited the proliferation of mouse B cell line BCL1. The IC50 was 4.9 μg/ml, 2.2 μM, and 1.0 μM, respectively.

In addition, in the mangosteen peel extract used in this experiment, α-mangosteen flavone and γ-mangosteen flavone contained 13.2% and 12.4%, respectively, considering the respective molecular weights of 410.466 and 396.439, and obtained by the following formula. :

The contribution rate of α-mangosteen flavone={(IC _{50 of} mangosteen peel extract) (μg/ml)×0.131÷410.466÷1000×10 ⁶ }÷(IC _{50 of} α-mangosteen flavone) (μM)×100

Contribution rate of γ-mangosteen flavonoids = {(IC _{50 of} mangosteen peel extract) (μg/ml) × 0.024 ÷ 396.439 ÷ 1000 × 10 ⁶ } ÷ (IC _{50 of} γ-mangosteen flavonoids) (μM) × 100

[Example 3] ‧ test method

Spleens were isolated from NC/Tnd mice (7 to 9 weeks old) in an SPF environment, homogenized in RPMI1640 medium, and a single cell suspension was prepared by a 70 μm mesh filter. After centrifugation (1200 rpm, 4 ° C, 5 minutes), the suspension was resuspended in a concentration of 1 × 10 ⁸ cells/ml in RoBosep buffer (Stemcell Technologies Inc, Vancouver, Canada, Cat. No. 20104). CD19-positive cells were isolated using ROBOSEP (Stemcell Technologies Inc, Vancouver, Canada, Cat. No. 20104) using a Mouse CD19 positive selection kit (Stemcell Technologies Inc, Vancouver, Canada, Cat. No. 20000). After centrifugation (1200 rpm, 4 ° C, 5 minutes), the concentration was 5×10 ⁵ cells/ml and suspended in RPMI1640 medium (containing 10% FCS, 50 U/ml PS, 1×10 ^-4 M 2-ME). . Simultaneously with 500 U/ml rmIL-4 (R&D system, Inc., Minneapolis, USA, Cat. No. 404-ML-010) and 10 μg/ml LPS (Sigma, St. Louis, USA, Cat. No. L6143) Add samples of each concentration to a 96-well plate (200 μl/well). Set the group to which no samples were added as the control group. After culturing for 9 days at 37 ° C under 5% CO ₂ , the culture supernatant was recovered, and the IgE concentration was determined by ELISA.

‧result

For B cells isolated from mouse spleen alone, mangosteen peel extract, α-mangosteen flavonoids, and γ-mangosteen flavone inhibited the production of IgE induced by IL-4 and LPS. The results are shown in Table 1 and Figure 2. The IC50 is 4.8 μg/ml, 2.5 μM, and 1.6 μM, respectively.

[Example 4] Effect on interleukin production in In vitro (in vitro manipulation) (analysis of the level of the message RNA (mRNA)) ‧ test method

Axillary lymph nodes were isolated from NC/Tnd mice (12-17 weeks old) with dermatitis in a conventional environment, and homogenized in RPMI1640 medium, and a single cell suspension was prepared by a 70 μm mesh filter. After centrifugation (1200 rpm, 4 ° C, 5 minutes), the concentration was 2 × 10 ⁶ cells / ml suspended in RPMI1640 medium (containing 10% FCS, 50 U / ml PS, 1 × 10 ^-4 M 2-ME) in. Simultaneously with 1 μg/ml serotonin (PWM; Sigma, St. Louis, USA, Cat. No. L6143), samples of each concentration were seeded in 24-well plates (1 ml/well) at 37 ° C, 5 Incubate for 24 hours under the conditions of % CO ₂ . A group in which no PWM was added was set as a control group (indicated by medium in FIGS. 3 and 4), and a group in which only PWM was added without adding a sample (indicated by PWM in FIGS. 3 and 4) was set. Thereafter, total RNA (total RNA) was isolated by TAKARA FastPure RNA Kit (TAKARA Bio Inc., Shiga, Japan, Cat. No. 9190) using TAKARA PrimeScript lst strand cDNA Synthesis kit (TAKARA Bio Inc., Shiga, Japan) , Cat. No. 6110A) to prepare cDNA and perform real-time PCR. Further, β-actin was used as an endogenous control, and comparison was performed by a comparative CT method (ΔΔCT method). The △ △ CT method is based on the theory that the difference detected in one cycle is twice the amount of difference in the amount of expression, compared with the group as the reference, and paying attention to the group to be investigated is several cycles earlier or Delay the number of cycles to reach the Threshold Line and quantify the amount of performance. In the ΔΔCT method, a group (medium) to which no PWM is added is used as a reference.

‧result

The results are shown in Figures 3 and 4. For lymphocytes isolated from mouse axillary lymph nodes, mangosteen peel extract, α-mangosteen flavonoids, and γ-mangosteen flavone inhibited the increase in mRNA expression of IFN-γ induced by PWM. The IC50 is 6.2 μg/ml, 3.6 μM, and 3.6 μM, respectively. On the other hand, IL-4, IL-5, and IL-13 were not shown to have significant inhibition.

[Example 5] Effect on TSLP production in In vitro (in vitro manipulation) (analysis at the mRNA level) ‧ test method

The newborns of NC/Tnd mice (1 to 3 days) were sacrificed and the skin was cut with scissors. After the subcutaneous fat was physically removed, a skin sample was taken by a 6 mm puncher. The skin sample was floated in a 0.25% trypsin-EDTA solution, incubated at 4 ° C for 1 hour, and then incubated at 37 ° C for 30 minutes. The epidermis was separately separated from the skin sample with forceps and allowed to float in the medium in a 24-well dish. Add various concentrations of the reagents, and add TNF-α (25 ng/ml) and IL-1β (10 ng/ml) at 37 ° C for 1 hour before the conditions of 37 ° C, 5% CO ₂ . Under cultivation. A group in which the reagent and TNF-α and IL-1β were not added (the leftmost side in FIG. 5) and a group in which only TNF-α and IL-1β were added (the second group in the left side in FIG. 5) were set. As a control group. After 24 hours, total RNA was extracted using TAKARA RNA Fastpure and subjected to real-time PCR. Again, β-actin was used as an intrinsic control and compared by the delta-ΔCT method. In the ΔΔCT method, the test drug and the group in which neither TNF-α nor IL-1β was added were used as a reference.

‧result

The results are shown in Figure 5. In the epidermal tissue culture system, the mangosteen peel extract and the α-mangosteen flavone showed an inhibitory effect on the expression of mRNA of TSLP induced by the co-addition of TNF-α and IL-1β.

[Example 6] ‧ test method

NC/Tnd mice (5-6 weeks old) with dermatitis not yet afflicted under normal conditions were divided into two groups, namely, the control feed administration group and the mangosteen injection group of the mixed bait feed group containing mangosteen peel extract. (each group n=7). In the conventional environment, no matter which group used the control feed for one week of preliminary breeding, they were allowed to freely ingest the test feed. That is, the mangosteen injection group was given a mixed bait feed containing 0.25% mangosteen peel extract (the intake of mangosteen peel extract was 250 mg/kg/day), and the control feed administration group was administered CRF-1 (Oriental yeast). the company). Six weeks after the test feed was administered, the mice were killed by cervical dislocation and skin samples were taken with a 6 mm punch.

The obtained skin samples were separately divided using TAKARA FastPure RNA kit (TAKARA Bio Inc., Shiga, Japan, Cat. No. 9190). From the whole RNA, the TAKARA PrimeScript lst strand cDNA Synthesis kit (TAKARA Bio Inc., Shiga, Japan, Cat. No. 6110A) was used for cDNA production, and in order to analyze various interleukins and chemokines, and nerve fibers. The mRNA expression of NGF, semaphorin 3a (Sema 3a), and cell proliferation control factor AQP3 related to stretch regulation was subjected to real-time PCR. Again, β-actin was used as an intrinsic control and compared by the delta-ΔCT method. In the ΔΔCT method, the control feed group was used as a reference.

‧result

The results are shown in Figure 6. In Fig. 6, the vertical axis is the relative value of 1 in the control feed group. In the mangosteen extract feed group, the mRNA expression levels of TSLP, IL-4, IFN-γ, CCL22 (MDC), CCL24 (Eotaxin-2), NGF and AQP3 were significantly decreased.

Claims (13)

An immunomodulator characterized by the extract of mangosteen peel. An immunomodulator as claimed in claim 1, which inhibits proliferation of cells. An immunomodulator as claimed in claim 1, which inhibits the production of IFN-γ. An immunomodulator as claimed in claim 1, which inhibits the production of TSLP. The immunomodulator of claim 2, wherein the cell is a cell of the type selected from the group consisting of keratinocytes, mast cells, and B cells. The immunomodulator of claim 1, which inhibits the production of at least one of IL-4, CCL22 (MDC), CCL24 (Eotaxin-2), NGF, AQP3. An immunomodulator characterized by being composed of α-mangosteen flavonoids. An immunomodulator as claimed in claim 7, which inhibits proliferation of cells. An immunomodulator as claimed in claim 7, which inhibits the production of at least one of IgE, IFN-γ or TSLP. An immunomodulator characterized by being composed of γ-mangosteen flavonoids. An immunomodulator as claimed in claim 10 which inhibits proliferation of cells. An immunomodulator as claimed in claim 10 which inhibits the production of at least one of IgE or IFN-γ. A food or drink for immunomodulation, which comprises the immunomodulator of any one of claims 1 to 12.