JP2022155522A - Agent for suppressing decreased immune function and method for suppressing decreased immune function - Google Patents
Agent for suppressing decreased immune function and method for suppressing decreased immune function Download PDFInfo
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Abstract
Description
本発明は、免疫機能低下抑制剤及び免疫機能の低下抑制方法に関する。 TECHNICAL FIELD The present invention relates to an agent for suppressing deterioration of immune function and a method for suppressing deterioration of immune function.
免疫グロブリンＡ（「免疫グロブリンＡ抗体」とも呼ばれる。以下、単に「ＩｇＡ」とも記載する。）は主に血清中と粘膜面に存在している。粘膜は、病原性のあるウィルスや細菌等を含む様々な異物と常に接している。そのため、粘膜面に分泌される分泌型ＩｇＡは、病原体の粘膜上皮細胞への付着・定着阻止、病原体から生産される毒素や酵素に対する中和作用等により、粘膜面の恒常性を維持するのに非常に重要な役割をもつ。ＩｇＡは主にパイエル板を含む腸管関連リンパ組織や粘膜関連リンパ組織において、ＩｇＭ＋Ｂ細胞からactivation-induced cytidine deaminase（ＡＩＤ）により誘導されるクラススイッチを経て分化したＩｇＡ産生細胞から産生される。ＩｇＡの産生経路はＢ細胞のクラススイッチ過程におけるＴ細胞の関与の有無により、Ｔ細胞依存的経路とＴ細胞非依存的経路の２つに大別される。Ｔ細胞依存的ＩｇＡはパイエル板などの胚中心に存在する濾胞性Ｔ細胞や濾胞性樹状細胞から刺激を受け、ＩｇＭ＋Ｂ細胞からクラススイッチしたＩｇＡ＋Ｂ細胞が抗体産生細胞に分化し、産生され、当該抗原に特異的に強く結合する。一方でＴ細胞非依存的ＩｇＡは腸管粘膜固有層に存在する樹状細胞やマクロファージなど自然免疫系細胞から刺激を受けてＩｇＭ＋Ｂ細胞からクラススイッチしたＩｇＡ＋Ｂ細胞がＩｇＡ産生細胞に分化し、産生され（非特許文献１）、不特定の様々な抗原に結合する。これらのＩｇＡ抗体は上皮細胞基底膜に発現するポリメリックＩｇ受容体（ｐＩｇＲ）がＪ鎖を介して多量体ＩｇＡ抗体と結合することで、上皮細胞に取り込まれ小胞体輸送により粘膜面へ分泌される。
Ｔ細胞非依存的経路ではＩｇＡの定常的な生産がなされており、このためＴ細胞非依存的産生経路によるＩｇＡの産生を向上できれば、獲得免疫が確立していない新規の抗原が粘膜面に接触しても即時に当該抗原を排除できる確率を高めて、免疫機能が向上すると考えられている。
Immunoglobulin A (also referred to as "immunoglobulin A antibody"; hereinafter also simply referred to as "IgA") is present mainly in serum and mucosal surfaces. Mucous membranes are constantly in contact with various foreign substances, including pathogenic viruses and bacteria. Therefore, secretory IgA, which is secreted on the mucosal surface, plays a role in maintaining the homeostasis of the mucosal surface by inhibiting the adhesion and colonization of pathogens to mucosal epithelial cells and by neutralizing toxins and enzymes produced by pathogens. It has a very important role. IgA is mainly produced from IgA-producing cells differentiated from IgM + B cells through class switching induced by activation-induced cytidine deaminase (AID) in gut-associated lymphoid tissues including Peyer's patches and mucosa-associated lymphoid tissues. IgA production pathways are roughly divided into T cell dependent pathways and T cell independent pathways depending on the presence or absence of the involvement of T cells in the class switching process of B cells. T cell-dependent IgA is stimulated by follicular T cells and follicular dendritic cells present in germinal centers such as Peyer's patches, and class-switched IgA + B cells from IgM + B cells differentiate into antibody-producing cells. It is produced and binds specifically and strongly to the antigen. On the other hand, T cell-independent IgA is stimulated by innate immune system cells such as dendritic cells and macrophages present in the intestinal lamina propria, and class-switched IgA + B cells from IgM + B cells differentiate into IgA-producing cells. , is produced (Non-Patent Document 1) and binds to a variety of unspecified antigens. These IgA antibodies are taken up by epithelial cells and secreted to the mucosal surface by endoplasmic reticulum transport by binding polymeric Ig receptors (pIgR) expressed on the epithelial cell basement membrane to multimeric IgA antibodies via the J chain. .
IgA is constantly produced by the T cell-independent pathway, so if IgA production by the T cell-independent production pathway can be improved, new antigens for which acquired immunity has not been established will come into contact with the mucosal surface. It is thought that the immune function is improved by increasing the probability that the antigen can be eliminated immediately even if it is.
一方、インターロイキン－６（英: Interleukin-6、以下「ＩＬ－６」とも記載する。）はＴ細胞やマクロファージ等の細胞により産生され、液性免疫を制御するサイトカインの一つである。ＩＬ－６は種々の生理現象や炎症・免疫疾患の発症メカニズムに関与している。ＩＬ－６は造血や炎症反応などにおいて重要な役割を果たすサイトカインであり、Ｂ細胞から抗体産生細胞への分化促進などの生理作用を示すほか、活性化した樹状細胞から分泌され、制御性Ｔ細胞の活性を抑えることや、Ｔ細胞サブセットの一つであるＴｈ１７細胞への分化促進を行うことが知られている。 On the other hand, interleukin-6 (English: Interleukin-6, hereinafter also referred to as "IL-6") is one of cytokines that is produced by cells such as T cells and macrophages and controls humoral immunity. IL-6 is involved in various physiological phenomena and onset mechanisms of inflammatory and immune diseases. IL-6 is a cytokine that plays an important role in hematopoiesis and inflammatory reactions. In addition to exhibiting physiological effects such as promoting the differentiation of B cells into antibody-producing cells, IL-6 is secreted from activated dendritic cells and regulates T It is known to suppress cell activity and promote differentiation into Th17 cells, which is one of the T cell subsets.
加齢や疲労等により免疫機能は低下することが知られており、免疫機能低下の例として、加齢や疲労等によるＩｇＡ産生量の低下が知られている。一般に免疫機能低下時には感染がおこりやすく、また重症化しやすい。免疫機能が低下するとＩＬ－６等の炎症性サイトカインが増加することが知られている。特に老化に伴い免疫機能低下と持続的な感染が悪循環となり、ＩＬ－６等の炎症性サイトカインが慢性的に増加して慢性炎症につながると考えられている（非特許文献２）。
従って、老化等の免疫機能が低下する状態においてＩｇＡの産生を促進する組成物が存在すれば、感染症の予防又は改善に特に効果的であると考えられる。また老化等の免疫機能が低下する状態において、ＩＬ－６の産生を抑制する免疫機能低下抑制剤は、特に慢性炎症等の炎症を効果的に予防又は改善できると考えられる。免疫機能が低下する状態においてＩＬ－６の産生を抑制できる免疫機能低下抑制剤は、免疫機能低下抑制機能に優れ、上記の慢性炎症等の炎症を効果的に予防又は改善でき、例えば当該炎症によって引き起こされる体組織の機能低下および免疫機能低下を更に効果的に抑制できると考えられる。
It is known that immune function declines due to aging, fatigue, and the like, and as an example of immune function decline, a decrease in IgA production due to aging, fatigue, and the like is known. In general, when the immune function is weakened, infection is likely to occur, and it is likely to become severe. It is known that inflammatory cytokines such as IL-6 increase when immune function declines. In particular, deterioration of immune function and persistent infection with aging become a vicious circle, which is thought to lead to chronic inflammation due to a chronic increase in inflammatory cytokines such as IL-6 (Non-Patent Document 2).
Therefore, if there is a composition that promotes the production of IgA in a state of weakened immune function such as aging, it would be particularly effective in preventing or ameliorating infectious diseases. In addition, in conditions such as aging where the immune function is weakened, it is believed that an immune function depression inhibitor that suppresses the production of IL-6 can effectively prevent or ameliorate inflammation such as chronic inflammation. An immune function depression inhibitor that can suppress the production of IL-6 in a state where immune function is depressed is excellent in immune function depression suppression function and can effectively prevent or ameliorate inflammation such as the chronic inflammation described above. It is thought that the induced functional deterioration of body tissues and immune dysfunction can be suppressed more effectively.
これまでに種々の物質による免疫グロブリンＡの産生促進、又はインターロイキン－６の産生抑制が報告されてきた（特許文献１～６）。 Various substances have been reported to promote the production of immunoglobulin A or suppress the production of interleukin-6 (Patent Documents 1 to 6).
上記の通り、老化などの免疫機能が低下する状態においてＩｇＡ産生を促進する成分は、感染症の予防又は改善に特に効果的であると考えられる。また、老化等の免疫機能が低下する状態においてＩＬ－６の産生を抑制する成分は、慢性炎症等の炎症の予防又は改善に特に効果的であると考えられる。
しかしながら、従来のＩｇＡ産生促進剤及びＩＬ－６産生抑制剤には、日常的に摂取するにはコストが高い、あるいは健康面での影響が懸念されるなどの問題が存在した。
As described above, components that promote IgA production in conditions such as aging where immune function is weakened are considered to be particularly effective in preventing or ameliorating infectious diseases. In addition, a component that suppresses the production of IL-6 in a state of weakened immune function such as aging is considered to be particularly effective in preventing or ameliorating inflammation such as chronic inflammation.
However, conventional IgA production promoters and IL-6 production inhibitors have problems such as high costs for daily intake and concerns about health effects.
従って、本発明の課題は、安価且つ安全で日常的に摂取でき、老化等による免疫機能の低下を効果的に改善できる新規の免疫機能低下抑制剤を提供することにある。 Accordingly, an object of the present invention is to provide a novel immune function depression inhibitor that is inexpensive, safe, can be taken on a daily basis, and can effectively improve the deterioration of immune function due to aging or the like.
本発明は鋭意検討した結果、驚くべきことに、小麦ブランを経口摂取することで、老化等の免疫機能が低下する状態において、腸管粘膜に分泌されるＩｇＡの産生を効果的に促進できること、また脾臓細胞から分泌されるＩＬ－６の産生を効果的に抑制できることを見出した。 As a result of intensive studies, the present invention surprisingly found that orally ingesting wheat bran can effectively promote the production of IgA secreted in the intestinal mucosa in a state of weakened immune function such as aging, and It was found that the production of IL-6 secreted from spleen cells can be effectively suppressed.
本発明は上記知見に基づくものであり、小麦ブランを含有し、ＩｇＡの産生促進に用いられる、免疫機能低下抑制剤を提供するものである。 The present invention is based on the above findings, and provides an immune function suppression inhibitor containing wheat bran and used for promoting IgA production.
また、本発明は、ＩｇＡの分泌が低下する状態におけるＩｇＡの産生促進に用いられる、前記免疫機能低下抑制剤を提供するものである。 In addition, the present invention provides the above-mentioned inhibitor for suppressing immune function deterioration, which is used for promoting IgA production in a state in which IgA secretion is reduced.
また、本発明は、小麦ブランを含有し、ＩＬ－６の産生の抑制に用いられる、免疫機能低下抑制剤を提供するものである。 In addition, the present invention provides an immunosuppressive agent containing wheat bran and used for suppressing IL-6 production.
また、本発明は、小麦ブランを含有し、ＩｇＡの産生の促進、及びＩＬ－６の産生抑制に用いられる、免疫機能低下抑制剤を提供するものである。 In addition, the present invention provides an immune function suppressing agent that contains wheat bran and is used for promoting IgA production and suppressing IL-6 production.
また、本発明は、小麦ブランを含有し、ＩｇＡの分泌が低下する状態におけるＩＬ－６の産生の抑制に用いられる、免疫機能低下抑制剤を提供するものである。 The present invention also provides an immune function depression inhibitor containing wheat bran and used for suppressing IL-6 production in a state where IgA secretion is reduced.
更に、本発明は、小麦ブランを用いてＩｇＡの産生を促進する、免疫機能の低下抑制方法を提供するものである。 Furthermore, the present invention provides a method for suppressing a decline in immune function, which uses wheat bran to promote IgA production.
更に、本発明は、小麦ブランを用いてＩｇＡの産生を促進し、且つ、ＩＬ－６の産生を抑制する、免疫機能の低下抑制方法を提供するものである。 Furthermore, the present invention provides a method for suppressing a decline in immune function by promoting IgA production and suppressing IL-6 production using wheat bran.
また、本発明は、小麦ブランを含有する、腸管上皮細胞におけるポリメリックＩｇ受容体（ｐＩｇＲ）の発現増強剤を提供するものである。 The present invention also provides an agent for enhancing the expression of polymeric Ig receptor (pIgR) in intestinal epithelial cells, which contains wheat bran.
本発明は、安全かつ安価であり、日常的に経口摂取でき、ＩｇＡの分泌低下等に示される老化等に伴う免疫機能低下を効果的に抑制できる免疫機能低下抑制剤及び免疫機能低下抑制方法を提供できる。
また本発明は、安全かつ安価であり、日常的に経口摂取でき、老化等の免疫機能が低下する状態において、ＩＬ－６産生を抑制して炎症を効果的に予防又は改善できる、免疫機能低下の抑制能に優れた免疫機能低下抑制剤及び免疫機能低下抑制方法を提供できる。
また本発明は、腸管上皮細胞におけるポリメリックＩｇ受容体（ｐＩｇＲ）の発現増強を通じて、ＩｇＡ産生及び管腔内分泌を効果的に促進できる剤を提供できる。
INDUSTRIAL APPLICABILITY The present invention provides a safe and inexpensive agent for suppressing the deterioration of immune function, which can be taken orally on a daily basis, and which can effectively suppress the deterioration of immune function associated with aging, etc., which is indicated by decreased secretion of IgA, etc., and a method for suppressing the deterioration of immune function. can provide.
In addition, the present invention is safe and inexpensive, can be taken orally on a daily basis, and can effectively prevent or improve inflammation by suppressing IL-6 production in conditions such as aging where immune function is weakened. It is possible to provide an agent for suppressing the deterioration of immune function and a method for suppressing the deterioration of immune function.
The present invention can also provide agents that can effectively promote IgA production and luminal secretion through enhancement of polymeric Ig receptor (pIgR) expression in intestinal epithelial cells.
以下、本発明を説明する。以下では、本発明の免疫機能低下抑制剤及びｐＩｇＲの発現増強剤をまとめて「本発明の剤」とも記載する。 The present invention will be described below. Hereinafter, the agent for suppressing deterioration of immune function and the agent for enhancing expression of pIgR of the present invention are collectively referred to as the "agent of the present invention".
本発明の剤は、小麦ブランを含有する。小麦ブランとは、小麦ふすまとも呼ばれ、一般的には、小麦種子の胚乳部や胚芽部から分離された、外皮（表皮ともいう）を含む画分のことである。小麦ブランは、小麦粒の外皮を主体とするものである。小麦ブランとしては、一般的な小麦粉の製造過程で生じる、小麦粒から胚乳を除去した残部、あるいはこの残部からさらに胚芽を除去したもの等を用いることができる。小麦ブランは、赤小麦及び白小麦のいずれに由来していてもよいが、赤小麦由来の小麦ブランは特徴ある風味を多く有するため、継続的に多量摂取できるようになり、本発明の効果を高めることにつながるため好ましい。 The agent of the present invention contains wheat bran. Wheat bran is called wheat bran, and is generally a fraction containing outer skin (also called epidermis) separated from the endosperm and germ of wheat seeds. Wheat bran is mainly composed of the outer skin of wheat grains. As the wheat bran, the residue obtained by removing the endosperm from the wheat grain, or the residue obtained by further removing the germ from the wheat grain, which is generated in the general manufacturing process of wheat flour, can be used. Wheat bran may be derived from either red wheat or white wheat, but since wheat bran derived from red wheat has a lot of characteristic flavor, it can be continuously ingested in large amounts, and the effect of the present invention is achieved. It is preferable because it leads to enhancement.
小麦ブランは、多くの食物繊維を含有している。本発明で用いる小麦ブランは、その食物繊維の多くが不溶性食物繊維であることが腸管を物理的に刺激しやすい点から好ましい。小麦ブラン中の不溶性食物繊維量としては、小麦ブランの乾燥質量に対して、例えば１５～６０質量％が好ましく例示され、２０～５５質量％がより好ましく、２０～５０質量％が特に好ましい。小麦ブラン中の不溶性食物繊維量は酵素―重量法（プロスキー変法）（AOAC991.43）で測定できる。また、本発明において、食物繊維中、不溶性食物繊維の割合は５０質量％以上であることが整腸性や抗メタボリックシンドロームの点で好ましく、８０質量％以上であることが特に好ましい。例えば、小麦ブランは、それを構成するアラビノキシランにおける５０質量％以上が整腸性等の理由から不溶性食物繊維であることが好ましく、８０質量％以上が不溶性食物繊維であることが好ましい。食物繊維の量は酵素―重量法（プロスキー変法）（AOAC991.43）にて測定できる。またアラビノキシラン量は酸分解後に高速液体クロマトグラフィーにてアラビノース、キシロース、ガラクトースを測定し、以下の式に代入することで測定できる。
アラビノキシラン含量＝0.88ｘ（アラビノース＋キシロース＋0.7ｘガラクトース）
Wheat bran contains a lot of dietary fiber. The wheat bran used in the present invention preferably contains insoluble dietary fiber because it is likely to physically stimulate the intestinal tract. The amount of insoluble dietary fiber in wheat bran is preferably 15 to 60% by mass, more preferably 20 to 55% by mass, and particularly preferably 20 to 50% by mass, based on the dry mass of wheat bran. The amount of insoluble dietary fiber in wheat bran can be determined by the enzyme-gravimetric method (modified Prosky method) (AOAC991.43). In the present invention, the ratio of insoluble dietary fiber in dietary fiber is preferably 50% by mass or more from the viewpoint of intestinal regulation and anti-metabolic syndrome, and particularly preferably 80% by mass or more. For example, in wheat bran, 50% by mass or more of arabinoxylan constituting it is preferably insoluble dietary fiber for reasons such as intestinal regulation, and 80% by mass or more is preferably insoluble dietary fiber. The amount of dietary fiber can be measured by the enzyme-gravimetric method (modified Prosky method) (AOAC991.43). Further, the amount of arabinoxylan can be measured by measuring arabinose, xylose and galactose by high performance liquid chromatography after acid decomposition and substituting in the following formula.
Arabinoxylan content = 0.88 x (arabinose + xylose + 0.7 x galactose)
本発明で用いる小麦ブランは、加熱処理されたものであることが、酵素活性を失活でき、小麦ブランを用いた加工適性を高められる点で好ましい。加熱処理としては、乾熱処理及び湿熱処理などが挙げられるが、乾熱処理は湿熱処理よりもより高温での処理が可能であり、小麦ブラン特有のえぐみを除去する効果を期待することができる。その結果、小麦ブランを継続的に多量摂取できることに繋がり、本発明の効果を高めることができるため好ましい。
加熱処理として乾熱処理を行う場合、小麦ブランの品温が好ましくは１００～１８０℃、更に好ましくは１２０～１６０℃となるようにして、好ましくは０～１２０分間、更に好ましくは１～６０分間処理を行う方法を例示できる。
It is preferable that the wheat bran used in the present invention is heat-treated, because the enzymatic activity can be deactivated and the processability using the wheat bran can be enhanced. Examples of heat treatment include dry heat treatment and wet heat treatment. Dry heat treatment can be performed at a higher temperature than wet heat treatment, and can be expected to have the effect of removing the harshness peculiar to wheat bran. As a result, a large amount of wheat bran can be ingested continuously, and the effect of the present invention can be enhanced, which is preferable.
When dry heat treatment is performed as heat treatment, the product temperature of wheat bran is preferably 100 to 180 ° C., more preferably 120 to 160 ° C., preferably for 0 to 120 minutes, more preferably 1 to 60 minutes. can be exemplified.
熱処理として湿熱処理を行う場合、水蒸気を導入する密閉系容器内において、小麦ブランの品温が、好ましくは８０～１３０℃、更に好ましくは８５～１１０℃となるようにして、好ましくは１～３００秒間、更に好ましくは１～６０秒間滞留させることにより行う方法を例示できる。 When wet heat treatment is performed as heat treatment, the product temperature of wheat bran is preferably 80 to 130 ° C., more preferably 85 to 110 ° C., preferably 1 to 300 in a closed container into which steam is introduced. Seconds, more preferably 1 to 60 seconds can be exemplified.
小麦ブランの形状としては、フレーク状、粒状、粉末状等が挙げられ特に限定されない。小麦ブランの粒径は特に限定されないが、例えば１０μｍ以上１０ｍｍ以下であることが入手容易性の点で好ましい。小麦ブランの粒径は例えばマイクロトラックMT3000 IIシリーズ（マイクロトラック・ベル株式会社）を用いて測定できる。より好ましくは上記粒径に粉砕してから、上記の加熱処理を行ったものであることが好ましい。 The shape of the wheat bran is not particularly limited and may be flaky, granular, powdery, or the like. Although the grain size of wheat bran is not particularly limited, it is preferably, for example, 10 μm or more and 10 mm or less in terms of availability. The grain size of wheat bran can be measured using, for example, Microtrac MT3000 II series (Microtrac Bell Co.). More preferably, the powder is pulverized to the above particle size and then subjected to the above heat treatment.
本発明の剤は、哺乳動物の免疫機能低下を抑制するために用いられる。哺乳動物としては、ヒトの他に、例えばイヌ、ネコ、マウス、ラット、ウサギ、ウシ、ウマ、サル等が含まれる。即ち、本発明の免疫機能低下抑制剤は、ヒトのみならず、ペット（愛玩動物）、家畜等に対しても適用可能である。本発明では、小麦ブランを哺乳動物全般に対して医療目的又は非医療目的で適用し得る。 The agent of the present invention is used to suppress immune dysfunction in mammals. Mammals include, in addition to humans, dogs, cats, mice, rats, rabbits, cows, horses, monkeys, and the like. In other words, the suppressing agent for the deterioration of immune function of the present invention can be applied not only to humans but also to pets (pet animals), domestic animals and the like. In the present invention, wheat bran can be applied to mammals in general for medical or non-medical purposes.
本発明において、「免疫機能低下」とは、老化、ストレス、激しい運動、不眠、疲労、外傷、疾病等により、免疫機能低下の原因のない状態（例えば若年期や健常時）に比べて免疫機能が低下することを指す。また「免疫機能が低下する状態」とは、老化、ストレス、激しい運動、不眠、疲労、外傷、疾病等により、免疫機能低下の原因のない状態（例えば若年期や健常時）に比べて免疫機能が低下しようとしている状態、低下中である状態、又は低下した状態を指す。本発明において、免疫機能低下を抑制する態様としては、免疫機能低下の予防又は改善のいずれであってもよい。免疫機能の低下の例としては、例えば老化、ストレス、激しい運動、不眠、疲労、外傷、疾病等に伴うＩｇＡなどの抗体の産生、分泌の低下が挙げられる。老化とは、一般に、加齢に伴う生理機能の低下を指すとされる。ここでいうＩｇＡの分泌としては、例えば頬側粘膜、胃粘膜、腸粘膜、嗅上皮、口腔粘膜、子宮内膜粘膜などの粘膜面におけるＩｇＡの分泌が挙げられる。例えば腸管腔へのＩｇＡの分泌量は、糞便中のＩｇＡ量をＥＬＩＳＡ法等により定量できるが、これに限定されない。免疫機能低下の程度としては、特に限定されないが、例えば、ＩｇＡの分泌量が基準状態に比べて低下した場合が例として挙げられる。ここでいう基準状態とは、例えばストレスや疲労による免疫機能の低下であれば、当該原因が存在する前の健康状態を指す。また老化状態であれば、例えば青年期（例えばヒトであれば２０代）の健康時が挙げられる。例えば後述する実施例では、コントロール食摂取群では青年期にあたる１２週齢のマウスのＩｇＡ分泌量（糞便中濃度）に対して、中年期（例えばヒトであれば３０代以降）にあたる２４週齢～２８週齢のＩｇＡ分泌量（糞便中濃度）が７５％以下に低減しているが、小麦ブラン含有食摂取群ではそのような大幅な低下が効果的に抑制されている。このように、本発明では、基準時から７５％以下とＩｇＡ分泌量が大幅に低下するような免疫機能低下状態におけるＩｇＡ産生を促進でき、免疫機能低下を効果的に予防又は改善できる。また本発明の剤は、老化等、比較的長期間に亘る免疫機能の低下に対しても、効果的に予防又は改善できる。 In the present invention, the term "immune function deterioration" means that aging, stress, strenuous exercise, insomnia, fatigue, trauma, disease, etc., compared to a state without a cause of immune function deterioration (e.g., young age or healthy state). refers to a decrease in In addition, "a state in which the immune function is weakened" means that the immune function is lower than that in a state (for example, young age or healthy state) where there is no cause for the deterioration of immune function due to aging, stress, strenuous exercise, insomnia, fatigue, trauma, disease, etc. is about to decline, is in the process of decline, or has declined. In the present invention, the aspect of suppressing the deterioration of immune function may be either prevention or improvement of the deterioration of immune function. Examples of decreased immune function include decreased production and secretion of antibodies such as IgA associated with aging, stress, strenuous exercise, insomnia, fatigue, injury, disease, and the like. Aging is generally considered to refer to the deterioration of physiological functions associated with aging. The secretion of IgA here includes, for example, secretion of IgA in mucosa surfaces such as buccal mucosa, gastric mucosa, intestinal mucosa, olfactory epithelium, oral mucosa, and endometrial mucosa. For example, the amount of IgA secreted into the intestinal lumen can be quantified by the ELISA method or the like for the amount of IgA in feces, but the method is not limited to this. Although the degree of immune function deterioration is not particularly limited, for example, a case where the amount of IgA secreted is reduced compared to the reference state can be mentioned. The reference state here refers to the state of health before the cause exists, for example, in the case of a decrease in immune function due to stress or fatigue. In the case of an aging state, for example, a healthy state in adolescence (for example, in the case of humans, in their twenties) can be mentioned. For example, in the examples described later, in the control diet intake group, the amount of IgA secretion (concentration in feces) of 12-week-old mice, which corresponds to adolescence, is compared to that of 24-week-old, which corresponds to middle age (for example, after 30s for humans). The amount of IgA secreted (concentration in feces) decreased to 75% or less at 28 weeks of age, but such a drastic decrease was effectively suppressed in the wheat bran-containing diet intake group. Thus, in the present invention, IgA production can be promoted in a state of immune dysfunction in which the IgA secretion level is significantly decreased to 75% or less from the baseline, and immune dysfunction can be effectively prevented or improved. In addition, the agent of the present invention can effectively prevent or ameliorate deterioration of immune function over a relatively long period of time, such as aging.
本発明の剤は、粘膜（例えば、頬側粘膜、胃粘膜、腸粘膜、嗅上皮、口腔粘膜、子宮内膜等、好ましくは腸粘膜）上への免疫グロブリンＡの分泌を促進することができる。これにより、粘膜免疫が活性化され、ウィルスや細菌などの病原体感染やその毒素による中毒等に対してより抵抗力が高まる。この観点から、本発明の剤の有効成分である小麦ブランは、粘膜（例えば、頬側粘膜、胃粘膜、腸粘膜、嗅上皮、口腔粘膜、子宮内膜等、好ましくは腸粘膜）における免疫機能の低下抑制剤の有効成分として有用である。また、本発明の剤は、腸管免疫機能の低下抑制剤の有効成分として有用できる。 The agent of the present invention can promote secretion of immunoglobulin A onto mucosa (e.g., buccal mucosa, gastric mucosa, intestinal mucosa, olfactory epithelium, oral mucosa, endometrium, etc., preferably intestinal mucosa). . As a result, mucosal immunity is activated, and resistance to infection with pathogens such as viruses and bacteria and poisoning due to their toxins is enhanced. From this point of view, wheat bran, which is an active ingredient of the agent of the present invention, has an immune function in mucosa (e.g., buccal mucosa, gastric mucosa, intestinal mucosa, olfactory epithelium, oral mucosa, endometrium, etc., preferably intestinal mucosa). is useful as an active ingredient of a decrease inhibitor. In addition, the agent of the present invention can be useful as an active ingredient of an agent for suppressing a decrease in intestinal immune function.
特に、本発明の剤は、抗原刺激によらずに産生されるＩｇＡの産生量を向上させるものであることが好ましい。抗原刺激によらずに産生されるＩｇＡとしては、Ｔ細胞非依存的ＩｇＡ産生経路によるＩｇＡの産生が挙げられる。抗原刺激によらない産生経路によるＩｇＡ産生は、定常的に行われている。また抗原刺激によらない産生経路により産生されたＩｇＡは、Ｔ細胞依存的ＩｇＡ産生経路により産生されたＩｇＡと異なり、多様な抗原に非特異的に結合する。従って、Ｔ細胞非依存的ＩｇＡ産生経路により産生されたＩｇＡは、新規の抗原が粘膜に接触した際に、新たな免疫感作のプロセスを経ることなく、即時に当該抗原の排除等が可能となり、免疫機能を向上させることができる。このため、本発明の剤は、新興含む感染症（例えば獲得免疫が確立していない新規の病原体に起因した感染症）に対する防御機能を向上させる、あるいは腸内細菌叢など腸管環境の恒常性を保つなどの使用方法が可能である。 In particular, the agent of the present invention preferably improves the amount of IgA produced without antigenic stimulation. Examples of IgA produced without antigenic stimulation include production of IgA by the T cell-independent IgA production pathway. IgA production by a production pathway that does not depend on antigenic stimulation is routinely performed. In addition, unlike IgA produced by the T cell-dependent IgA production pathway, IgA produced by a production pathway that does not depend on antigen stimulation nonspecifically binds to various antigens. Therefore, IgA produced by the T cell-independent IgA production pathway can eliminate the antigen immediately without undergoing a new immunization process when the new antigen comes into contact with the mucosa. , can improve immune function. Therefore, the agent of the present invention improves the defense function against infectious diseases including emerging (for example, infectious diseases caused by new pathogens for which acquired immunity has not been established), or improves the homeostasis of the intestinal environment such as intestinal flora. It is possible to use such as keeping.
更に、本発明の剤は、ＩＬ－６の産生を効果的に抑制できる。特に本発明の剤は、老化、ストレス、激しい運動、不眠、疲労、外傷、疾病等の、免疫機能が低下する状態において、ＩＬ－６の産生を効果的に抑制でき、これにより慢性炎症等の炎症を効果的に抑制できる。本発明の剤は、例えば脾臓細胞におけるＩＬ－６の産生を効果的に抑制できる。本発明においてＩＬ－６の産生抑制により予防又は改善することが可能な炎症の例としては、大腸炎、小腸炎、関節リュウマチ等の自己免疫疾患、アルツハイマー病などの神経炎症、歯周病、動脈硬化等が挙げられる。例えば後述する実施例では、コントロール食摂取群では青年期にあたる１２週齢のマウスのＩｇＡ分泌量（糞便中濃度）に対して、中年期（例えばヒトであれば３０代後半又はそれ以降）にあたる２８週齢のＩｇＡ分泌量（糞便中濃度）が７５％以下に低減しているが、小麦ブラン含有食摂取群ではそのような大幅な低下が効果的に抑制されている。このように、本発明では、基準時から７５％以下とＩｇＡ分泌量が大幅に低下するような免疫機能低下状態におけるＩＬ－６産生を抑制でき、免疫機能低下に伴う炎症を効果的に予防又は改善できる。また本発明の剤は、老化等、比較的長期間に亘る免疫機能の低下に伴う炎症に対しても、効果的に予防又は改善できる。 Furthermore, the agent of the present invention can effectively suppress IL-6 production. In particular, the agent of the present invention can effectively suppress the production of IL-6 in conditions such as aging, stress, strenuous exercise, insomnia, fatigue, injury, disease, etc., in which immune function is lowered, thereby preventing chronic inflammation and the like. It can effectively suppress inflammation. The agent of the present invention can effectively suppress IL-6 production in, for example, splenocytes. Examples of inflammation that can be prevented or improved by suppressing IL-6 production in the present invention include autoimmune diseases such as colitis, enteritis, rheumatoid arthritis, neuroinflammation such as Alzheimer's disease, periodontal disease, arterial curing and the like. For example, in the examples described later, in the control diet intake group, the amount of IgA secretion (concentration in feces) of 12-week-old mice, which corresponds to adolescence, corresponds to middle age (e.g., late 30s or later for humans). At 28 weeks of age, the amount of IgA secreted (concentration in feces) decreased to 75% or less, but such a drastic decrease was effectively suppressed in the wheat bran-containing diet intake group. Thus, in the present invention, it is possible to suppress IL-6 production in a state of reduced immune function in which the amount of IgA secretion is significantly reduced to 75% or less from the baseline, and effectively prevent or prevent inflammation associated with reduced immune function. It can be improved. In addition, the agent of the present invention can effectively prevent or improve inflammation associated with deterioration of immune function over a relatively long period of time, such as aging.
なお、本発明の剤は、腸管上皮細胞におけるポリメリックＩｇ受容体（ｐＩｇＲ）の発現増強剤としても使用できる。 The agent of the present invention can also be used as an agent for enhancing the expression of polymeric Ig receptor (pIgR) in intestinal epithelial cells.
本発明の剤は、哺乳動物の医薬品、医薬部外品又は食品として、あるいはそれらを製造するために使用することができる。ここでいう「食品」は、食品全般を包含し、いわゆる健康食品を含む一般食品の他、厚生労働省の保健機能食品制度に規定される特定保健用食品や栄養機能食品等の保健機能食品、サプリメント等を包含し、さらには動物に給餌される家畜用飼料、ペットフードも包含する。本発明の剤は、小麦ブランを有効成分として含有し、且つ免疫機能低下抑制を企図して、その旨を表示した医薬品、医薬部外品又は食品として使用することができる。 The agent of the present invention can be used as pharmaceuticals, quasi-drugs or foods for mammals, or for producing them. The term “food” here includes general food including so-called health food, food with health claims such as food for specified health use and food with nutrient function claims specified in the food with health claims system of the Ministry of Health, Labor and Welfare, and supplements. etc., and also includes livestock feed and pet food fed to animals. The agent of the present invention contains wheat bran as an active ingredient, and can be used as a drug, quasi-drug, or food that is labeled to that effect, with the intention of suppressing a decline in immune function.
本発明の剤を医薬品又は医薬部外品として使用する場合、有効成分である小麦ブランを単独で含有していても良く、又は、さらに薬学的に許容される担体を含有していても良く、又は、小麦ブランによる免疫機能低下抑制、ＩｇＡ産生増加又はＩＬ－６産生抑制、ｐＩｇＲの発現増強剤の効果が損なわれない範囲でさらに他の有効成分や薬理成分を含有していても良い。斯かる担体としては、例えば、賦形剤、被膜剤、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、希釈剤、分散剤、緩衝剤、浸透圧調整剤、ｐＨ調整剤、乳化剤、防腐剤、安定剤、酸化防止剤、着色剤、紫外線吸収剤、保湿剤、増粘剤、活性増強剤、抗炎症剤、殺菌剤、矯味剤、矯臭剤等が挙げられる。 When the agent of the present invention is used as a drug or quasi-drug, it may contain wheat bran as an active ingredient alone, or may contain a pharmaceutically acceptable carrier, Alternatively, it may further contain other active ingredients and pharmacological ingredients as long as the effects of wheat bran for suppressing immune function deterioration, increasing IgA production or suppressing IL-6 production, and enhancing the expression of pIgR are not impaired. Such carriers include, for example, excipients, coating agents, binders, extenders, disintegrants, surfactants, lubricants, diluents, dispersants, buffers, osmotic pressure adjusters, pH adjusters, Examples include emulsifiers, preservatives, stabilizers, antioxidants, colorants, ultraviolet absorbers, moisturizers, thickeners, activity enhancers, anti-inflammatory agents, bactericides, corrigents, corrigents and the like.
本発明の剤を医薬品又は医薬部外品として使用する場合、任意の投与形態で投与され得る。投与形態は、経口投与でも非経口投与でも良い。例えば、経口投与形態としては、錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤のような固形投薬形態、並びにエリキシル、シロップ及び懸濁液のような液体投薬形態が挙げられ、非経口投与形態としては、注射、輸液、経皮、経粘膜、経鼻、経腸、吸入、坐剤、ボーラス、貼布剤等が挙げられる。このうち、経口投与形態が好ましい。 When the agent of the present invention is used as a drug or quasi-drug, it can be administered in any dosage form. The dosage form may be oral administration or parenteral administration. For example, oral dosage forms include solid dosage forms such as tablets, coated tablets, granules, powders, capsules, and liquid dosage forms such as elixirs, syrups and suspensions; Examples include injection, infusion, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus, patch and the like. Of these, oral dosage forms are preferred.
本発明の剤を食品として使用する場合、有効成分である前記小麦ブランを単独で含有していても良く、又は、記小麦ブランによる免疫機能低下抑制効果が損なわれない範囲でさらに、医薬品、医薬部外品、食品の製造に用いられる種々の添加剤を含有していても良い。斯かる添加剤としては、例えば、各種油脂、生薬、アミノ酸、多価アルコール、天然高分子、ビタミン、食物繊維、界面活性剤、精製水、賦形剤、安定剤、ｐＨ調整剤、酸化防止剤、甘味料、呈味成分、有機酸などの酸味料、安定剤、フレーバー、着色料、香料等が挙げられる。 When the agent of the present invention is used as a food, it may contain the wheat bran, which is an active ingredient, alone, or it may be further added to a pharmaceutical product, medicine, as long as the effect of suppressing the deterioration of immune function by the wheat bran is not impaired. It may contain various additives used in the production of quasi-products and foods. Examples of such additives include various fats and oils, crude drugs, amino acids, polyhydric alcohols, natural polymers, vitamins, dietary fibers, surfactants, purified water, excipients, stabilizers, pH adjusters, antioxidants. , sweeteners, taste components, acidulants such as organic acids, stabilizers, flavors, coloring agents, fragrances, and the like.
本発明の小麦ブランを食品として使用する場合、その形態は特に限定されないが、例えば、その形態としては、固形、半固形又は液状であり得、錠剤形態、丸剤形態、カプセル形態、液剤形態、シロップ形態、粉末形態、顆粒形態等が挙げられる。具体的な食品の形態としては、パン類、麺類、ゼリー状食品や各種スナック類、焼き菓子、ケーキ類、チョコレート、ガム、飴、タブレット、カプセル、スープ類、乳製品、冷凍食品、インスタント食品、サプリメント、その他加工食品及びそれらの材料等が挙げられる。 When the wheat bran of the present invention is used as food, its form is not particularly limited. syrup form, powder form, granule form and the like. Specific food forms include breads, noodles, jellied foods, various snacks, baked goods, cakes, chocolates, gums, candies, tablets, capsules, soups, dairy products, frozen foods, instant foods, Supplements, other processed foods and materials thereof, and the like.
本発明の剤中における小麦ブランの含有量は、特に制限されるものではなく、剤型、適用対象（哺乳動物）の症状や年齢性別などによって適宜調整可能であるが、ヒトを対象とする場合、通常、本発明の剤の小麦ブランの摂取量が乾燥質量にて成人１人１日当たり５ｇ以上であることが好ましく、８ｇ以上であることが特に好ましい。上限としては、例えば５０ｇ以下であることが副作用を避ける点から好ましく、４５ｇ以下であることが特に好ましい。本発明の剤における小麦ブランの割合は特に限定されず、例えば１質量％以上、或いは３質量％以上、或いは、３０質量％以上、或いは５０質量％以上等の種々の割合が挙げられる。
本発明の剤は、日常的に摂取し続けることが可能であり、例えば２週間以上継続して経口摂取することが可能である。１週間のうち、経口摂取は毎日であってもよく、１又は複数日であってもよい。
The content of wheat bran in the agent of the present invention is not particularly limited, and can be appropriately adjusted depending on the dosage form, symptoms and age and sex of the target (mammals), but when targeting humans Generally, the intake of wheat bran in the agent of the present invention is preferably 5 g or more, particularly preferably 8 g or more, per adult per day in terms of dry mass. From the viewpoint of avoiding side effects, the upper limit is preferably 50 g or less, and particularly preferably 45 g or less. The proportion of wheat bran in the agent of the present invention is not particularly limited, and includes various proportions such as 1% by mass or more, 3% by mass or more, 30% by mass or more, or 50% by mass or more.
The agent of the present invention can be continuously ingested on a daily basis, for example, it can be orally ingested continuously for two weeks or longer. During the week, oral intake may be daily, or may be on one or more days.
本発明には、下記＜１＞～＜５＞の形態が含まれる。
＜１＞健康維持、美容等の非医療目的で小麦ブランを生体に摂取させて免疫グロブリンＡの産生を促進する、免疫機能の低下抑制方法。
＜２＞健康維持、美容等の非医療目的で、免疫グロブリンＡの分泌が低下する状態における免疫グロブリンＡの産生促進に用いられる、＜１＞に記載の免疫機能低下抑制剤。
＜３＞健康維持、美容等の非医療目的で小麦ブランを生体に摂取させてインターロイキン６産生を抑制する、免疫機能の低下抑制方法。
＜４＞健康維持、美容等の非医療目的で小麦ブランを生体に摂取させて免疫グロブリンＡの産生を促進し、且つ、インターロイキン６産生を抑制する、免疫機能の低下抑制方法。＜５＞健康維持、美容等の非医療目的で小麦ブランを生体に摂取させて免疫グロブリンＡの分泌が低下する状態におけるインターロイキン６の産生を抑制する、免疫機能低下抑制方法。
The present invention includes the following modes <1> to <5>.
<1> A method for suppressing a decline in immune function, comprising promoting the production of immunoglobulin A by ingesting wheat bran for non-medical purposes such as health maintenance and beauty care.
<2> The agent for suppressing the deterioration of immune function according to <1>, which is used for promoting the production of immunoglobulin A in a state in which the secretion of immunoglobulin A is reduced for non-medical purposes such as health maintenance and beauty care.
<3> A method for suppressing a decline in immune function, comprising allowing a living body to ingest wheat bran for non-medical purposes such as health maintenance and beauty care, thereby suppressing interleukin-6 production.
<4> A method for suppressing a decline in immune function, comprising promoting the production of immunoglobulin A and suppressing the production of interleukin 6 by ingesting wheat bran for non-medical purposes such as health maintenance and beauty care. <5> A method for suppressing a decline in immune function, comprising allowing a living body to ingest wheat bran for non-medical purposes such as health maintenance and beauty care, thereby suppressing the production of interleukin 6 in a state where the secretion of immunoglobulin A is reduced.
以下、実施例に基づいて本発明を説明するが、本発明は下記実施例に限定されるものではない。 EXAMPLES The present invention will be described below based on examples, but the present invention is not limited to the following examples.
実施例１
（実施方法）
本試験は２０１７年度（２０１７年４月１日から、２０１８年３月３１日までの間）に実施した。ＮＭＦ飼料（オリエンタル酵母工業（株）製）で飼育したＤＯ１１．１０雌性マウス（１０～１２週齢）にＡＩＮ－９３Ｍ精製飼料（オリエンタル酵母工業（株）製）を１週間自由摂取させた後、糞便を採集、市販マウスＩｇＡ測定キット（Bethyl Laboratories, Inc、商品名 IgA, Mouse, ELISA Quantitation Set）で糞便中ＩｇＡ値を測定した。得られたＩｇＡ値に基づき、群間有意差が生じないように各群６匹、２群に分けた（１１週）。
それぞれの群にＡＩＮ－９３Ｍ精製飼料をさらに１週間自由摂取させた後（１２週）、ＡＩＮ－９３Ｍ精製飼料を摂取させる群を対照区（コントロール食摂取群）、ＡＩＮ－９３Ｍ精製飼料に含まれるセルロースパウダーの代わりに加熱処理した赤小麦のブランを５％（ｗ／ｗ）添加した改変ＡＩＮ－９３Ｍ精製飼料を摂取させる群を試験区（ブラン含有食摂取群）とした。各群の食餌配合を下記表１に示す。
Example 1
(Implementation method)
This test was conducted in fiscal year 2017 (from April 1, 2017 to March 31, 2018). DO11.10 female mice (10 to 12 weeks old) bred with NMF feed (manufactured by Oriental Yeast Co., Ltd.) were given AIN-93M purified feed (manufactured by Oriental Yeast Co., Ltd.) ad libitum for 1 week. Feces were collected, and fecal IgA values were measured using a commercially available mouse IgA measurement kit (Bethyl Laboratories, Inc, trade name: IgA, Mouse, ELISA Quantitation Set). Based on the obtained IgA values, the rats were divided into 2 groups of 6 rats each so that there would be no significant difference between the groups (11 weeks).
After allowing each group to freely ingest AIN-93M purified feed for an additional week (12 weeks), the group ingesting AIN-93M purified feed is a control group (control diet intake group), included in AIN-93M purified feed A group fed with modified AIN-93M refined feed to which 5% (w/w) of heat-treated red wheat bran was added instead of cellulose powder was used as a test group (bran-containing food intake group). The diet composition of each group is shown in Table 1 below.
その後、１６週間飼育する中、２週間毎（１４、１６、１８、２０、２２、２４、２６、２８の各週）に糞便を回収し、糞便中ＩｇＡ値（ｎｇ／糞ｍｇ）を測定した。なお小麦ブランの加熱処理は乾熱処理として１２０～１５０℃、６０分間とした。また、用いた小麦ブランは上記の範囲の平均粒径を有するものであった。また上記の通り、用いた小麦ブランは赤小麦由来であった。また用いた小麦ブラン（加熱処理後の小麦ブラン）の不溶性食物繊維量は３３質量％であり、食物繊維中の不溶性食物繊維の割合は８９．５質量％であった。
得られた各週の糞便中ＩｇＡ量（ｎｇ／糞ｍｇ）の平均値とその標準偏差を図１に示す。
After that, during the 16 weeks of breeding, feces were collected every two weeks (
FIG. 1 shows the mean value and standard deviation of the fecal IgA level (ng/mg feces) obtained for each week.
試験終了後（２８週）に、投与期間終了直後マウスから各々脾臓細胞を定法により採取した。脾臓を２ｍｌの基本培地（ＲＰＭＩ１６４０培地）を入れたディッシュ内で摩砕し、基本培地が６ｍｌ入った１５ｍｌのコニカルチューブに入れた後よく懸濁し、１分間静置し、浮遊細胞の入った画分をコニカルチューブに移し、４℃、３００Ｇ前後で遠心分離にかけ、ペレット状にした。ペレットを、ウシ胎児血清（ＦＣＳ）を１０容量％濃度で含有する培養培地（シグマアルドリッチ社製）４ｍＬで再懸濁した。この細胞を、１ウェルに３×１０５個入れ、培養培地３００μｌ／ウェル、抗原である卵白アルブミンを、ウェル中の培地量に対して１．５μＭ及び７．５μＭの濃度で添加した状態で、３７℃、ＣＯ２５容量％のインキュベーターにて培養、抗原特異的免疫応答を惹起し、添加７２時間後における培養上清中のインターロイキン－６産生量を比較した。インターロイキン－６は市販サイトカイン測定キット（eBioscience社製）で評価した。インターロイキン－６の量はコントロール食摂取群マウス由来の脾臓細胞の産生した値の平均値を１００％とした相対値として示した。結果を図２及び図３に示す。 After the end of the test (28 weeks), spleen cells were collected from each mouse by a standard method immediately after the end of the administration period. The spleen was triturated in a dish containing 2 ml of basal medium (RPMI1640 medium), placed in a 15 ml conical tube containing 6 ml of basal medium, suspended well, left to stand for 1 minute, and the fraction containing floating cells was removed. Aliquots were transferred to conical tubes and centrifuged at around 300G at 4°C to pellet. The pellet was resuspended in 4 mL of culture medium (Sigma-Aldrich) containing fetal calf serum (FCS) at a concentration of 10% by volume. 3×10 5 of these cells were placed in one well, and 300 μl/well of culture medium and ovalbumin as an antigen were added at concentrations of 1.5 μM and 7.5 μM relative to the amount of medium in the well. The cells were cultured in an incubator at 37° C. and 5% by volume of CO 2 to induce an antigen-specific immune response, and the amount of interleukin-6 produced in the culture supernatant 72 hours after the addition was compared. Interleukin-6 was evaluated using a commercially available cytokine assay kit (manufactured by eBioscience). The amount of interleukin-6 was shown as a relative value, with the mean value of the spleen cells derived from the control-fed mice taken as 100%. The results are shown in FIGS. 2 and 3. FIG.
両側スチューデント分析によれば、図１における糞便中ＩｇＡ量では、１８週、２０週、２２週、２６週において、コントロール食摂取群とブラン食摂取群との間にｐ＜０．０５の有意差が確認された。ここで、図１の通り、マウスのＩｇＡ分泌量は、コントロール食摂取群では１２週齢から１６週齢にかけて低下し、１７週齢以降に更に低下する。一方、小麦ブラン含有食摂取群では、老化に伴うＩｇＡ分泌量の低下が有意に抑制されていることが判る。 According to two-sided Student's analysis, there was a significant difference of p<0.05 between the control diet intake group and the bran diet intake group in the fecal IgA level in FIG. was confirmed. Here, as shown in FIG. 1, the IgA secretion level of the mice in the control diet intake group decreases from 12 weeks of age to 16 weeks of age, and further decreases after 17 weeks of age. On the other hand, it can be seen that in the wheat bran-containing food intake group, the decline in IgA secretion due to aging was significantly suppressed.
ここで、ＤＯ１１．１０雌性マウスはそのＴ細胞のほとんどが特異的抗原に応答性を有するＴ細胞レセプター（ＴＣＲ）を発現するマウス（ＴＣＲトランスジェニックマウスともいう。）であり、前記特異的抗原以外の抗原に対する免疫応答性が著しく低い。そのため、ＴＣＲトランスジェニックマウスを、前記特異的抗原に曝露されない環境下で飼育することにより、抗原刺激によらずに定常的に産生される抗体の量を安定的に定量することができる。上記の試験では、ＤＯ１１．１０雌性マウスを、特異的抗原である卵白アルブミン等に暴露させない環境下で飼育しているため、図１に示すＩｇＡ分泌量は、抗原刺激によらずに定常的に産生されるＩｇＡ分泌量である。 Here, the DO11.10 female mouse is a mouse expressing a T cell receptor (TCR) in which most of its T cells are responsive to a specific antigen (also referred to as a TCR transgenic mouse). immune responsiveness to antigens of Therefore, by breeding TCR transgenic mice in an environment in which they are not exposed to the specific antigen, the amount of antibody that is constantly produced without antigenic stimulation can be stably quantified. In the above test, DO11.10 female mice were bred in an environment where they were not exposed to specific antigens such as ovalbumin, so the IgA secretion shown in FIG. Amount of IgA secretion produced.
また両側スチューデント分析によれば、図２及び図３に示すＩＬ－６量では抗原投与量が１．５μＭ及び７．５μＭのいずれの場合においても、コントロール食摂取群と、ブラン含有食摂取群とで、ｐ＜０．０１の有意差が確認された。この通り、中年期に当たる２８週齢のＩＬ－６産生量がコントロール食群に比してブラン含有食摂取群では有意に抑制されていた。 Further, according to the two-sided Student's analysis, in the IL-6 amounts shown in FIGS. A significant difference of p<0.01 was confirmed. As can be seen, the amount of IL-6 produced at 28 weeks of age, which corresponds to middle age, was significantly suppressed in the bran-containing diet intake group compared to the control diet group.
実施例２
（実施方法）
以下用いた小麦ブランは実施例１と同様のものであった。つまり、加熱処理として１２０～１５０℃、６０分間の乾熱処理を施したものであった。また、用いた小麦ブランは１０μｍ以上１０ｍｍ以下の粒径を有するものであった。また用いた小麦ブランは赤小麦由来であった。また用いた小麦ブラン（加熱処理後の小麦ブラン）の不溶性食物繊維量は３３質量％であり、食物繊維中の不溶性食物繊維の割合は８９．５質量％であった。
小麦ブラン１ｇをメタノール洗浄済みの海砂と混合し、高速溶媒抽出機（ＡＳＥ－３５０、サーモフィッシャーサイエンティフィック）を用いて、酢酸酸性メタノール（容量比メタノール９０：水９．５：酢酸０．５）により加温抽出（８０℃、４サイクル）し、小麦ブラン抽出物を得た。溶媒を減圧流去後、１ｍｌのＤＭＳＯに再溶解し、ＦＣＳを含まないＥ‐ＭＥＭ培地で２００倍に希釈したものをサンプルとした。また、ＦＣＳを含まないＥ‐ＭＥＭ培地でＤＭＳＯを２００倍に希釈したものをネガティブコントロールとした。
ＨＴ－２９細胞（ECA:UK Health Security Agency由来、株式会社ケー・エー・シー社）を１０容量％ＦＣＳ含有Ｅ‐ＭＥＭ培地に懸濁し、３．０×１０５ｃｅｌｌｓ／ｗｅｌｌになるよう、１２ｗｅｌｌ ｐｌａｔｅに播種した。播種２日後、細胞をＨａｎｋｓ（－）で２回洗浄し、上記サンプルを１ｍｌずつｗｅｌｌに入れた。４８時間後に培養上清回収後、ＰＢＳ（－）、もしくはＨａｎｋｓ（－）で細胞表面を２回洗浄し、ＲＩＰＡ Ｌｙｓｉｓ ｂｕｆｆｅｒ（ATTO、使用時１ｍｌに対しＩｎｈｉｂｉｔｏｒを１０μｌ混合、氷冷）し、それを０．３ｍｌずつウェルに加え氷上で１５分間静置した。それを遠心チューブにうつし、１７，０００Ｇで５～１０分間遠心後、遠心上清を新しいチューブに回収した。
遠心上清に含まれるｐＩｇＲをＥＬＩＳＡ法（Ｈｕｍａｎ ｐＩｇＲ ＥＬＩＳＡ Ｐａｉｒ Ｓｅｔ、SinoBiological）、で測定した。９６ウェルプレートに、１次抗体の溶解液を１００μＬ／ウェル加え、４℃で終夜インキュベートし、吸引後に洗浄液を３００μＬ／ウェル加えての洗浄を２回繰り返し、ブロッキング液を３００μＬ／ウェル加えて１時間インキュベートした。これを吸引後に再度洗浄し、先ほどの遠心上清を１００μＬ／ウェル加えて２時間インキュベートした後に、洗浄した。２次抗体を含む溶液を１００μＬ／ウェル加え、１時間インキュベートした後、洗浄した。反応基質の溶液を２００μＬ／ウェル加え、室温で２０分間インキュベートしてから、停止液を５０μＬ加え、４５０ｎｍの吸光度を測定した。また、遠心上清の代わりに標準物質の各濃度溶液を調製してウェルに加え、得られた結果から検量線を作成してｐＩｇＲの発現量を定量した。この時、遠心上清の総タンパク質含量を測定しておき、タンパク含量あたりのｐＩｇＲと補正して評価した。結果を図４に示す。なお、ネガティブコントロールについて、同様に測定したタンパク含量あたりのｐＩｇＲを１００％としたときの値を発現量とした。
Example 2
(Implementation method)
The wheat bran used below was the same as in Example 1. That is, dry heat treatment was performed at 120 to 150° C. for 60 minutes as heat treatment. The wheat bran used had a particle size of 10 μm or more and 10 mm or less. The wheat bran used was also derived from red wheat. The amount of insoluble dietary fiber in the wheat bran used (heat-treated wheat bran) was 33% by mass, and the ratio of insoluble dietary fiber in the dietary fiber was 89.5% by mass.
1 g of wheat bran was mixed with methanol-washed sea sand, and acetic acid acid methanol (volume ratio methanol 90: water 9.5: acetic acid 0.5) was extracted using a high-speed solvent extractor (ASE-350, Thermo Fisher Scientific). Heated extraction (80° C., 4 cycles) was carried out according to 5) to obtain a wheat bran extract. After removing the solvent under reduced pressure, the solution was redissolved in 1 ml of DMSO and diluted 200-fold with FCS-free E-MEM medium to prepare a sample. A 200-fold dilution of DMSO in FCS-free E-MEM medium was used as a negative control.
HT-29 cells (derived from ECA: UK Health Security Agency, KAC Co., Ltd.) were suspended in E-MEM medium containing 10% by volume of FCS, and 12 wells were obtained so as to have 3.0×10 5 cells/well. Seeded on a plate. Two days after seeding, the cells were washed twice with Hanks (-), and 1 ml of the above sample was added to each well. After 48 hours, the culture supernatant was collected, the cell surface was washed twice with PBS (-) or Hanks (-), and RIPA lysis buffer (ATTO, mixed 1 ml with 10 μl of inhibitor when used, ice-cooled). was added to the wells in 0.3 ml portions and allowed to stand on ice for 15 minutes. It was transferred to a centrifugation tube, centrifuged at 17,000 G for 5 to 10 minutes, and the centrifugation supernatant was collected in a new tube.
pIgR contained in the centrifugation supernatant was measured by ELISA method (Human pIgR ELISA Pair Set, SinoBiological). Add 100 μL/well of the primary antibody solution to a 96-well plate, incubate overnight at 4° C., aspirate, add 300 μL/well of the washing solution and repeat washing twice, add 300 μL/well of the blocking solution for 1 hour. incubated. After aspirating, the plate was washed again, 100 μL/well of the above centrifugation supernatant was added, incubated for 2 hours, and then washed. A solution containing a secondary antibody was added at 100 μL/well, incubated for 1 hour, and then washed. After adding 200 μL/well of reaction substrate solution and incubating for 20 minutes at room temperature, 50 μL of stop solution was added and absorbance at 450 nm was measured. In addition, instead of the centrifugation supernatant, each concentration solution of the standard substance was prepared and added to the wells, and a standard curve was drawn from the obtained results to quantify the expression level of pIgR. At this time, the total protein content of the centrifugation supernatant was measured and evaluated after correction with pIgR per protein content. The results are shown in FIG. Regarding the negative control, the expression level was defined as the value when pIgR per protein content measured in the same manner was taken as 100%.
小麦ブラン抽出物を本細胞試験で評価すると、ｐＩＧＲの発現量が増加することを確認した。ＨＴ－２９細胞は腸管上皮細胞のモデルとして一般的に使用される細胞である。粘膜固有層で産生された二量体ＩｇＡは、上皮細胞に発現しているｐＩｇＲと結合し、細胞内を輸送されて管腔内に分泌されることが公知である。よって、小麦ブランを摂取すると、腸管上皮細胞においてｐＩｇＲの発現を高め、ＩｇＡの管腔内分泌が促進され、ＩｇＡ分泌が増加していたと考えられる。
When the wheat bran extract was evaluated in this cell test, it was confirmed that the expression level of pIGR was increased. HT-29 cells are cells commonly used as a model for intestinal epithelial cells. It is known that dimeric IgA produced in the lamina propria binds to pIgR expressed in epithelial cells, is transported intracellularly, and is secreted into the lumen. Therefore, it is considered that intake of wheat bran increased the expression of pIgR in intestinal epithelial cells, promoted luminal secretion of IgA, and increased IgA secretion.
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| JP7287665B2 (en) | 2019-06-24 | 2023-06-06 | 国立研究開発法人農業・食品産業技術総合研究機構 | Method for evaluating the ability of test substances to suppress age-related decline in mucosal immune function |
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