JP2005035896A - Immunopotentiator - Google Patents
Immunopotentiator Download PDFInfo
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- JP2005035896A JP2005035896A JP2003197511A JP2003197511A JP2005035896A JP 2005035896 A JP2005035896 A JP 2005035896A JP 2003197511 A JP2003197511 A JP 2003197511A JP 2003197511 A JP2003197511 A JP 2003197511A JP 2005035896 A JP2005035896 A JP 2005035896A
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- Coloring Foods And Improving Nutritive Qualities (AREA)
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Abstract
Description
【0001】
【発明の属する技術分野】
本発明は、糖類を有効成分とする免疫賦活剤に関する。さらに詳しくは、本発明は、従来免疫賦活作用が知られていなかった糖類、例えば、マンノオリゴ糖を有効成分として含有する、マクロファージのIL−12産生能増強作用を有する免疫賦活剤に関する。
【0002】
【従来の技術】
ヒトを初めとする生体は、侵入してくる外来微生物、ならびに内因性の腫瘍細胞のような異物的自己物質などに絶えずさらされている。これらに起因する各種の疾病に対抗するための生体防御機構として、免疫系を備えている。免疫反応の様式を大きく分類すると、免疫細胞自身が異物を攻撃排除する細胞性免疫と、免疫細胞が産生する抗体によって異物を排除する液性免疫とがある。
【0003】
免疫応答の初期の段階で重要な役割を果たす免疫系細胞の一つに、マクロファージが挙げられる。マクロファージは、侵入した微生物、ならびに個体の形態形成過程あるいは生体の体内に生じた不要なアポトーシス細胞や壊死細胞を、選択的に捕食し、消化分解して、これらを抗原としてリンパ球に提示する。また、マクロファージの表面には、Toll−like receptorと呼ばれる糖鎖をパターン認識して刺激を伝える受容体が存在している。マクロファージは、これらの過程で、種々のサイトカインやケモカインを産生し、生体防御応答に関与する他の細胞機能を制御する。例えば、マクロファージが産生するインターロイキン12(IL−12)は、ナチュラルキラー(NK)細胞を活性化するほか、抗原未感作のナイーブT細胞をTh1に分化させ、Th1/Th2バランスをTh1優位にし、免疫様式を細胞性免疫主体に導く作用があることが知られている。
【0004】
近年日本では、加速度的に高齢化社会を迎えつつあり、加齢による免疫力低下により高齢者がウイルス・微生物感染により死に至るケースが少なくない。また、多忙な現代社会およびストレスを受けやすい環境の中での食事の不規則な摂取も免疫力低下の原因となることが知られており、その対策が強く望まれている。その対処法として新規な抗腫瘍剤やワクチン、抗生物質の開発が精力的に行われている。しかし、これら治療剤は副作用が生じることが問題点であり、また最近は医療費が急増しており、食事の改善による医療費の低減が強く求められている。
【0005】
糖類は、古くから食経験があるため、何らかの生理活性を有するならば、比較的安全な治療剤になり得る。例えば、D−マンノースは生体内において、高マンノース型糖鎖に見られるように糖鎖の構成成分として存在しており、生命活動を維持している上で重要な役割を担っていることが認識されつつある。また、D−マンノースはサルモネラ菌のニワトリ腸管上皮細胞への定着を阻害する作用を有することが知られており(非特許文献1)、畜産分野において有害菌の感染を予防する飼料添加剤としての利用が提案されている(特許文献1および2)。
【0006】
しかし、病原性微生物やウイルスの感染防御、腫瘍細胞の破壊などの働きを担う細胞性免疫系の免疫細胞(マクロファージ、キラーT細胞、NK細胞など)を活性化するサイトカインであるIL−12の産生が、これらの糖質により増強されることは、従来知られていなかった。これまでに、このような機能を有する糖鎖としては、ニゲロオリゴ糖(非特許文献2、特許文献3)、ラフィノース(特許文献4および5)、ネオアガロオリゴ糖(特許文献6)、およびβ1,3グルカン(特許文献7)について報告されているに過ぎない。なお、イソマルトオリゴ糖の混合物については、Tリンパ球およびBリンパ球を増加させる作用が確認されているが、IL−12の産生増強については全く知られていない(特許文献8)。
【0007】
【特許文献1】
特開2001−213781号公報
【特許文献2】
特開平8−38064号公報
【特許文献3】
特開2002−80364号公報
【特許文献4】
特開2001−288093号公報
【特許文献5】
特開2001−288094号公報
【特許文献6】
特開2002−193828号公報
【特許文献7】
特開平11−246435号公報
【特許文献8】
特許第2729820号公報
【非特許文献1】
Poultry、Science, 68巻, 1351−1360頁, 1989年
【非特許文献2】
Murosakiら、Biosci. Biotechnol. Biochem., 63巻, 373頁, 1999年
【0008】
【発明が解決しようとする課題】
本発明は、免疫賦活作用を有し、食品素材としても利用可能な安全な免疫賦活剤を提供することを目的とする。
【0009】
【課題を解決するための手段】
本発明者らは、食品素材、特に糖類が免疫系に与える影響に関して鋭意研究を行った結果、マンノオリゴ糖に免疫賦活作用があることを見出し、本発明を完成した。
【0010】
すなわち、本発明は、マンノオリゴ糖を有効成分として含有する、免疫賦活剤を提供する。
【0011】
好適な実施態様では、上記マンノオリゴ糖は、α−1,2マンノビオース、α−1,3マンノビオース、およびα−1,4マンノビオースからなる群より選択される少なくとも1種である。
【0012】
より好適な実施態様では、上記免疫賦活剤は、さらに乳酸菌を有効成分として含有する。
【0013】
さらに好適な実施態様では、上記免疫賦活剤は、インターロイキン12の産生量を上昇させる作用を有する。
【0014】
【発明の実施の形態】
本発明の免疫賦活剤は、有効成分として、マンノオリゴ糖を含有する。
【0015】
マンノオリゴ糖は、D−グルコースの2−エピマーの単糖であるD−マンノースから構成されるオリゴ糖である。特に、α−1,2マンノビオースおよびα−1,3マンノビオースは、N−結合型糖タンパク質糖鎖に見られるように、糖鎖の構成単位として存在している。糖鎖は、生体内において細胞−細胞間の相互作用、細胞−基質接着、細菌・ウイルス−宿主相互作用など、生命活動を維持していく上で重要な役割を担っていることが明らかにされつつある。そのため、これらのマンノオリゴ糖は、従来のオリゴ糖には見られない新たな機能が見出されることが期待される。
【0016】
例えば、コーヒー抽出残渣から抽出したマンナンを加水分解して得られる、マンノースを主構成成分とするβ−1,4結合のマンノオリゴ糖について、腸内細菌の資化性、難う蝕性、および低カロリー性が報告されている(特開2001−149041号公報)。このように、種々のマンノオリゴ糖の生理機能については、現在のところ、ほとんど知られていない。
【0017】
本発明においては、主として二糖〜六糖のマンノオリゴ糖が用いられ、α−1,2結合、α−1,3結合、α−1,4結合、またはα−1,6結合しているものが好ましい。良好な免疫賦活作用が得られる点で、α−1,2マンノビオース、α−1,3マンノビオース、およびα−1,4マンノビオースからなる群より選択される少なくとも1種が特に好ましい。これらの糖類は、単独で用いても、あるいは2種以上を混合して用いてもよい。
【0018】
本発明の免疫賦活剤は、さらに乳酸菌を有効成分として含有することが好ましい。乳酸菌としては、食品の加工などに通常用いられる乳酸菌類が用いられ、特に、ヒトの腸内に棲んでいる腸内乳酸菌類が好適である。代表的には、ラクトバチルス・ガセリ、ラクトバチルス・カゼイ、ラクトバチルス・アシドフィルス、ビフィドバクテリウム・ロンガム、ビフィドバクテリウム・インファンティス、ビフィドバクテリウム・ビフィダム、ビフィドバクテリウム・ブレーべ、ビフィドバクテリウム・アドレッセンテス、ストレプトコッカス・フェカリスなどが挙げられる。これらは、単独で用いてもよく、あるいは2種以上を組み合わせて用いてもよい。
【0019】
本発明の免疫賦活剤は、上記糖類を単独でまたは組み合わせて、あるいは上記乳酸菌との混合物として用いることにより、マクロファージのIL−12の産生能を増強することができる。
【0020】
本発明の免疫賦活剤は、上記の有効成分を、通常用いられる食品あるいは食品成分、医薬担体または賦形剤と、通常用いられる方法で混合して、免疫力を高める食品や医薬品とすることができる。用いる食品あるいは食品成分、医薬担体または賦形剤は特に限定するものではなく、目的とする免疫賦活剤の具体的用途に応じて適宜選択できる。また、免疫賦活剤の形態も特に限定するものではなく、具体的用途に応じて、種々の固体や液体の形態とすることができる。
【0021】
本発明の免疫賦活剤を食品として用いる場合、調味料、畜肉加工品、農産加工品、菓子などの形態で提供することも可能である。
【0022】
【実施例】
(調製例)
乳酸菌培養培地であるMRS培地(商品名「Lactobacilli MRS Broth」、Difco社製)5mlにラクトバチルス/ガセリ ATCC 33323を接種し、32℃で24時間静置培養した。この培養液を100mlのMRS培地に1%になるように接種し、32℃で24時間静置培養した。得られた培養液を10,000×gで20分間遠心分離し、菌体を回収した。この菌体を生理食塩水に懸濁し、10,000×gで20分間遠心分離し、菌体を回収した。この操作を3回繰り返した後、菌体を蒸留水に懸濁した。この懸濁液を70℃に10分間置いて殺菌した後、ドライアイス−エタノール中で急速凍結した。これを凍結乾燥し、ラクトバチルス・ガセリ乾燥死菌体0.25gを得た。
【0023】
(実施例)
マウス由来のマクロファージの細胞株であるJ774細胞株(理化学研究所より入手可能)を、細胞数が5×106/mlとなるように、10%FBS(ウシ胎児血清)を含むDMEM培地(以下、単に培地という)で希釈した。これを96穴組織培養プレートに1穴当たり100μlを播種し、37℃の5%炭酸ガス培養器内で2時間培養した。これに上記調製例で得たラクトバチルス・ガセリ乾燥死菌体を4μg/mlの濃度で培地に分散させた懸濁液を1穴当たり50μl加え、さらに、表1に記載の糖をそれぞれ4μg/mlの濃度で培地に含む溶液を1穴当たり50μl加えた(最終濃度1μg/ml)。比較としてラクトバチルス・ガセリ乾燥死菌体を2μg/mlの濃度で培地に分散させた懸濁液またはラクトバチルス・ガセリ乾燥死菌体およびニゲロースを含む懸濁液を、あるいは対照として培地のみを、1穴当たり100μl加えた。これらを5%炭酸ガス培養器内で37℃にて24時間培養後、培養上清のIL−12をエンザイムイムノアッセイで測定した。
【0024】
IL−12のエンザイムイムノアッセイは以下のように行った。一次抗体としてラット抗マウスIL−12p40抗体(Genzyme社製)をPBSで4μg/mlに調製し、この一次抗体溶液を、96穴組織培養プレートに1穴当たり50μl加え、室温で一晩放置して、ラット抗マウスIL−12p40抗体を各穴に付着させた。PBSで洗浄後、1%ウシ血清アルブミン(BSA)を含むPBSを1穴当たり100μl加え、室温で1時間放置した。洗浄後、上記培養上清を1穴当たり50μl加え、室温で2時間放置し、培養上清中のIL−12をプレートに付着したラット抗マウスIL−12p40抗体と結合させた。洗浄後、二次抗体(検出抗体)のペルオキシダーゼ標識抗マウスIL−12p40抗体(Genzyme社製)を50μl加え、プレートに結合させたIL−12に結合させた。洗浄後、テトラメチルベンジジン(Dako Cytomation社製)を1穴当たり50μl加え、室温で20分間反応させた後、2N硫酸を1穴当たり50μl加えて反応を停止させた。マイクロプレートリーダーで450nmでの吸光度を測定し、リコンビナントマウスIL−12(Genzyme社製)を用いて作成した標準曲線から、培養上清中のIL−12の濃度を求めた。表1にその結果を示す。
【0025】
【表1】
【0026】
表1からわかるように、実験に用いたいずれの糖においても、IL−12産生能を増強することが知られているニゲロースを用いた場合と同等またはそれ以上のIL−12濃度を示した。さらに、乳酸菌(ラクトバチルス・ガセリ)だけを用いた場合も、IL−12の産生量は増加したが、糖を同時に用いることによって、IL−12の産生量がさらに増加した。このことから、本実験に用いた糖は、特に乳酸菌と組み合わせて用いることにより、マクロファージのIL−12産生能を増強することがわかった。
【0027】
【発明の効果】
本発明の免疫賦活剤は、IL−12の産生を増強するため、細胞性免疫賦活作用を有する。そのため、癌の免疫療法や癌の予防への利用が期待される。また、本発明の免疫賦活剤の有効成分は、従来から食品として用いられている糖および/または乳酸菌であり、安全であることが知られているため、医薬品としてだけでなく、健康食品としても利用可能である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an immunostimulant containing saccharide as an active ingredient. More specifically, the present invention relates to an immunostimulant having an effect of enhancing the ability to produce IL-12 of macrophages, which contains a saccharide, for example, manno-oligosaccharide, which has not been known to have an immunostimulatory action as an active ingredient.
[0002]
[Prior art]
Living organisms such as humans are constantly exposed to invading foreign microorganisms and foreign self-substances such as endogenous tumor cells. An immune system is provided as a biological defense mechanism for combating various diseases caused by these diseases. The types of immune responses can be broadly classified into cellular immunity, in which immune cells themselves attack and eliminate foreign substances, and humoral immunity, in which foreign substances are eliminated by antibodies produced by immune cells.
[0003]
One immune system cell that plays an important role in the early stages of the immune response is macrophages. Macrophages selectively prey on invading microorganisms and unnecessary apoptotic cells and necrotic cells generated in the morphogenesis process of the individual or in the body of the organism, digesting and decomposing them, and presenting these as antigens to lymphocytes. In addition, on the surface of macrophages, there are receptors called sugar-chain receptors called Toll-like receptors that transmit stimulation. In these processes, macrophages produce various cytokines and chemokines and control other cellular functions involved in biological defense responses. For example, interleukin 12 (IL-12) produced by macrophages activates natural killer (NK) cells, differentiates naïve T cells that have not been antigen-sensitized into Th1, and makes Th1 / Th2 balance superior to Th1. It is known that it has the effect of leading the immunity mode to cellular immunity.
[0004]
In recent years, in Japan, an aging society is accelerating, and there are many cases in which elderly people die due to viral or microbial infections due to a decrease in immunity due to aging. In addition, it is known that irregular intake of meals in a busy modern society and an environment susceptible to stress may cause a decrease in immunity, and countermeasures are strongly desired. As a countermeasure, new antitumor agents, vaccines, and antibiotics have been actively developed. However, these therapeutic agents are problematic in that they have side effects, and recently, medical expenses have increased rapidly, and there is a strong demand for reducing medical expenses by improving meals.
[0005]
Since saccharides have a long dietary experience, they can be a relatively safe therapeutic agent if they have some physiological activity. For example, D-mannose is recognized in vivo as a constituent component of a sugar chain as seen in high-mannose sugar chains, and plays an important role in maintaining life activity. It is being done. In addition, D-mannose is known to have an action of inhibiting Salmonella colonization in chicken intestinal epithelial cells (Non-patent Document 1), and is used as a feed additive for preventing infection of harmful bacteria in the field of livestock. Has been proposed (Patent Documents 1 and 2).
[0006]
However, production of IL-12, which is a cytokine that activates immune cells (macrophages, killer T cells, NK cells, etc.) of the cellular immune system that plays a role in protecting against pathogenic microorganisms and viruses and destroying tumor cells. However, it has not been known so far that it is enhanced by these carbohydrates. So far, sugar chains having such functions include nigerooligosaccharide (Non-patent Documents 2 and 3), raffinose (Patent Documents 4 and 5), neoagaro-oligosaccharide (Patent Document 6), and β1,3. Only glucan (Patent Document 7) has been reported. In addition, about the mixture of isomaltoligosaccharide, although the effect | action which increases T lymphocyte and B lymphocyte was confirmed, it is not known at all about the production enhancement of IL-12 (patent document 8).
[0007]
[Patent Document 1]
JP 2001-213781 A [Patent Document 2]
JP-A-8-38064 [Patent Document 3]
JP 2002-80364 A [Patent Document 4]
JP 2001-288093 A [Patent Document 5]
JP 2001-288094 A [Patent Document 6]
JP 2002-193828 A [Patent Document 7]
Japanese Patent Laid-Open No. 11-246435 [Patent Document 8]
Japanese Patent No. 2729820 [Non-Patent Document 1]
Poultry, Science, 68, 1351-1360, 1989 [Non-patent Document 2]
Murosaki et al., Biosci. Biotechnol. Biochem. 63, 373, 1999 [0008]
[Problems to be solved by the invention]
An object of the present invention is to provide a safe immunostimulant that has an immunostimulatory action and can be used as a food material.
[0009]
[Means for Solving the Problems]
As a result of intensive studies on the effects of food materials, particularly saccharides, on the immune system, the present inventors have found that manno-oligosaccharides have an immunostimulatory action and completed the present invention.
[0010]
That is, the present invention provides an immunostimulant containing mannooligosaccharide as an active ingredient.
[0011]
In a preferred embodiment, the manno-oligosaccharide is at least one selected from the group consisting of α-1,2 mannobiose, α-1,3 mannobiose, and α-1,4 mannobiose.
[0012]
In a more preferred embodiment, the immunostimulant further contains lactic acid bacteria as an active ingredient.
[0013]
In a more preferred embodiment, the immunostimulant has an action of increasing the production amount of interleukin 12.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
The immunostimulant of the present invention contains mannooligosaccharide as an active ingredient.
[0015]
Manno-oligosaccharide is an oligosaccharide composed of D-mannose, which is a 2-epimer monosaccharide of D-glucose. In particular, α-1,2 mannobiose and α-1,3 mannobiose exist as structural units of sugar chains as seen in N-linked glycoprotein sugar chains. It has been clarified that sugar chains play important roles in maintaining vital activities such as cell-cell interactions, cell-substrate adhesion, and bacteria / virus-host interactions in vivo. It's getting on. Therefore, these manno-oligosaccharides are expected to find new functions not found in conventional oligosaccharides.
[0016]
For example, regarding β-1,4-linked mannooligosaccharides, which are obtained by hydrolyzing mannan extracted from a coffee extraction residue and have mannose as a main constituent, enteric bacteria assimilation, caries resistance, and low calories Has been reported (Japanese Patent Laid-Open No. 2001-190441). Thus, little is known at present about the physiological functions of various manno-oligosaccharides.
[0017]
In the present invention, disaccharide to hexasaccharide manno-oligosaccharides are mainly used, which are α-1,2 bond, α-1,3 bond, α-1,4 bond, or α-1,6 bond. Is preferred. In view of obtaining a good immunostimulatory action, at least one selected from the group consisting of α-1,2 mannobiose, α-1,3 mannobiose, and α-1,4 mannobiose is particularly preferable. These saccharides may be used alone or in admixture of two or more.
[0018]
The immunostimulant of the present invention preferably further contains lactic acid bacteria as an active ingredient. As the lactic acid bacteria, lactic acid bacteria usually used for processing foods are used, and intestinal lactic acid bacteria living in the human intestine are particularly suitable. Typically, Lactobacillus gasseri, Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium bifidum, Bifidobacterium breve , Bifidobacterium addressenses, Streptococcus faecalis and the like. These may be used alone or in combination of two or more.
[0019]
The immunostimulant of the present invention can enhance the IL-12 production ability of macrophages by using the saccharides alone or in combination or as a mixture with the lactic acid bacteria.
[0020]
The immunostimulant of the present invention may be a food or pharmaceutical that enhances immunity by mixing the above active ingredients with a commonly used food or food ingredient, pharmaceutical carrier or excipient by a commonly used method. it can. The food or food ingredient, pharmaceutical carrier or excipient to be used is not particularly limited and can be appropriately selected depending on the specific use of the target immunostimulator. In addition, the form of the immunostimulant is not particularly limited, and can be in the form of various solids or liquids depending on the specific application.
[0021]
When using the immunostimulant of this invention as a foodstuff, it is also possible to provide with forms, such as a seasoning, livestock meat processed goods, agricultural processed goods, and confectionery.
[0022]
【Example】
(Preparation example)
Lactobacillus / gasseri ATCC 33323 was inoculated into 5 ml of MRS medium (trade name “Lactobacilli MRS Broth”, manufactured by Difco), which is a culture medium for lactic acid bacteria, and left to stand at 32 ° C. for 24 hours. This culture solution was inoculated to 100 ml of MRS medium so as to be 1%, followed by stationary culture at 32 ° C. for 24 hours. The obtained culture solution was centrifuged at 10,000 × g for 20 minutes, and the cells were collected. The cells were suspended in physiological saline and centrifuged at 10,000 × g for 20 minutes to collect the cells. After repeating this operation three times, the cells were suspended in distilled water. This suspension was sterilized by placing it at 70 ° C. for 10 minutes, and then quickly frozen in dry ice-ethanol. This was freeze-dried to obtain 0.25 g of dried dead cells of Lactobacillus gasseri.
[0023]
(Example)
A D774 medium containing 10% FBS (fetal calf serum) (hereinafter referred to as J774 cell line (available from RIKEN)), which is a mouse-derived macrophage cell line, so that the cell number is 5 × 10 6 / ml Diluted simply with medium). This was seeded in a 96-well tissue culture plate at 100 μl per well and cultured in a 5% carbon dioxide incubator at 37 ° C. for 2 hours. To this was added 50 μl of a suspension obtained by dispersing Lactobacillus gasseri dried dead cells obtained in the above Preparation Example in a medium at a concentration of 4 μg / ml, and each of the sugars shown in Table 1 was added at 4 μg / ml. 50 μl of the solution contained in the medium at a concentration of ml was added per well (final concentration 1 μg / ml). As a comparison, a suspension in which Lactobacillus gasseri dried dead cells were dispersed in a medium at a concentration of 2 μg / ml or a suspension containing Lactobacillus gasseri dried dead cells and nigerose, or only the medium as a control, 100 μl was added per well. These were cultured in a 5% carbon dioxide incubator at 37 ° C. for 24 hours, and IL-12 in the culture supernatant was measured by enzyme immunoassay.
[0024]
The enzyme immunoassay for IL-12 was performed as follows. A rat anti-mouse IL-12p40 antibody (Genzyme) was prepared as a primary antibody to 4 μg / ml with PBS, and 50 μl of this primary antibody solution was added to a 96-well tissue culture plate per well and left at room temperature overnight. Rat anti-mouse IL-12p40 antibody was attached to each hole. After washing with PBS, 100 μl of PBS containing 1% bovine serum albumin (BSA) was added per well and left at room temperature for 1 hour. After washing, 50 μl of the culture supernatant was added per well and allowed to stand at room temperature for 2 hours to bind the IL-12 in the culture supernatant to the rat anti-mouse IL-12p40 antibody attached to the plate. After washing, 50 μl of a secondary antibody (detection antibody) peroxidase-labeled anti-mouse IL-12p40 antibody (Genzyme) was added and allowed to bind to IL-12 bound to the plate. After washing, 50 μl of tetramethylbenzidine (manufactured by Dako Cytomation) was added per well and reacted at room temperature for 20 minutes. Then, 50 μl of 2N sulfuric acid was added per well to stop the reaction. Absorbance at 450 nm was measured with a microplate reader, and the concentration of IL-12 in the culture supernatant was determined from a standard curve prepared using recombinant mouse IL-12 (Genzyme). Table 1 shows the results.
[0025]
[Table 1]
[0026]
As can be seen from Table 1, in any sugar used in the experiment, an IL-12 concentration equal to or higher than that in the case of using nigerose known to enhance IL-12 production ability was shown. Furthermore, when only lactic acid bacteria (Lactobacillus gasseri) were used, the production amount of IL-12 was increased, but the production amount of IL-12 was further increased by simultaneously using sugar. From this, it was found that the sugar used in this experiment enhances the IL-12 production ability of macrophages, particularly when used in combination with lactic acid bacteria.
[0027]
【The invention's effect】
Since the immunostimulant of the present invention enhances IL-12 production, it has a cellular immunostimulatory effect. Therefore, it is expected to be used for cancer immunotherapy and cancer prevention. In addition, since the active ingredient of the immunostimulant of the present invention is sugar and / or lactic acid bacteria conventionally used as foods and is known to be safe, not only as pharmaceuticals but also as health foods Is available.
Claims (4)
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS58212780A (en) * | 1982-06-07 | 1983-12-10 | Yakult Honsha Co Ltd | Growth promoting substance for microorganism of genus bifidobacterium |
JPH067159A (en) * | 1990-12-27 | 1994-01-18 | Tokyo Tanabe Co Ltd | Selective growth promoter for bifidobacterium |
JP2001149041A (en) * | 1999-09-14 | 2001-06-05 | Ajinomoto General Foods Inc | Composition based on mannooligosaccharides |
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Publication number | Priority date | Publication date | Assignee | Title |
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JPS58212780A (en) * | 1982-06-07 | 1983-12-10 | Yakult Honsha Co Ltd | Growth promoting substance for microorganism of genus bifidobacterium |
JPH067159A (en) * | 1990-12-27 | 1994-01-18 | Tokyo Tanabe Co Ltd | Selective growth promoter for bifidobacterium |
JP2001149041A (en) * | 1999-09-14 | 2001-06-05 | Ajinomoto General Foods Inc | Composition based on mannooligosaccharides |
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