JP2022091605A - Immunopotentiator - Google Patents
Immunopotentiator Download PDFInfo
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- JP2022091605A JP2022091605A JP2020204528A JP2020204528A JP2022091605A JP 2022091605 A JP2022091605 A JP 2022091605A JP 2020204528 A JP2020204528 A JP 2020204528A JP 2020204528 A JP2020204528 A JP 2020204528A JP 2022091605 A JP2022091605 A JP 2022091605A
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- Prior art keywords
- tea
- black tea
- test
- immunity
- respiratory tract
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Abstract
Description
本発明は、免疫増強剤に関するものである。 The present invention relates to an immunopotentiator.
急性上気道炎症は主に上気道へのウイルス感染によって引き起こされる臨床症候群である。この疾患には、ライノウイルス、コロナウイルス、アデノウイルス、インフルエンザ、パラインフルエンザおよび呼吸器合胞体ウイルスを含む広範囲のウイルスが関与することが知られている（非特許文献１）。インフルエンザウイルス複製阻害剤を除いて根本的な治療薬や治療法はないが、健常な感染者であれば通常は、自己免疫力により医学的介入がなくとも一週間程度で回復する。 Acute upper respiratory tract inflammation is a clinical syndrome primarily caused by viral infections of the upper respiratory tract. It is known that a wide range of viruses including rhinovirus, coronavirus, adenovirus, influenza, parainfluenza and respiratory symptom virus are involved in this disease (Non-Patent Document 1). There is no radical cure or cure other than influenza virus replication inhibitors, but healthy infected individuals usually recover in about a week due to autoimmunity without medical intervention.
一方で、高齢者や慢性呼吸器疾患を有する免疫系が弱い患者では、副次的な細菌感染によって症状の重症度が高まる。急性上気道炎症の初期症状は喉や鼻などの不快感があり、その後に鼻詰まりや咽頭痛、さらには発熱による倦怠感や頭痛を生じる。これら症状はＱＯＬ低下のみならず、ウイルスの伝播は集団感染を引き起こし、休業や休校によって大きな経済的損失が生じる。米国では、インフルエンザ以外の上気道感染症による経済的影響は年間８７０億ドルと推定されている（非特許文献２）。 On the other hand, in the elderly and patients with a weak immune system with chronic respiratory illness, secondary bacterial infections increase the severity of symptoms. The initial symptoms of acute upper respiratory tract inflammation are discomfort in the throat and nose, followed by nasal congestion and throat pain, as well as fatigue and headache due to fever. These symptoms not only reduce the quality of life, but the transmission of the virus causes outbreaks, and the leave of absence or school closure causes great economic loss. In the United States, the economic impact of upper respiratory tract infections other than influenza is estimated to be $ 87 billion annually (Non-Patent Document 2).
植物に含まれるポリフェノール成分は、様々な動植物感染症の原因となるウイルスに対して抗ウイルス作用を示すことが知られている。Ｉｎ ｖｉｔｒｏ研究では、ポリフェノールがエンベロープなどのウイルス体のタンパク質と結合し、ウイルスが宿主細胞へ吸着して感染するのを阻害することや、細胞内での増殖を抑制する作用があることが報告されている（非特許文献３、４）。このため、ポリフェノールの抗ウイルス作用は、有用かつ安全性の高い感染症対策の一つ手段として応用が期待されている。 Polyphenol components contained in plants are known to exhibit antiviral activity against viruses that cause various animal and plant infectious diseases. In vitro studies have reported that polyphenols bind to proteins in viral bodies such as envelopes, inhibiting the virus from adsorbing to host cells and infecting them, and suppressing their growth inside cells. (Non-Patent Documents 3 and 4). Therefore, the antiviral action of polyphenols is expected to be applied as one of the useful and safe measures against infectious diseases.
チャノキ（Ｃａｍｅｌｌｉａ ｓｉｎｅｎｓｉｓ）の生葉には、カテキン類をはじめとしたポリフェノール成分を乾燥重量あたりで約２０％含有し、チャノキの葉や茎などを加工して製造される「茶」（緑茶、紅茶、烏龍茶など）の抽出液は、ポリフェノール成分を豊富に含有している飲料である。紅茶には、酵素酸化発酵の製造工程におけるカテキンの酸化生成物としてテアフラビン類、テアシネンシン類、テアルビジンなどの紅茶特有のポリフェノールが含まれる。その中で、テアフラビン類には、ウイルス粒子の感染性に直接影響を及ぼし、インフルエンザウイルスをｉｎ ｖｉｔｒｏで不活化するのに優れていることが分かっている（非特許文献５）。さらにテアフラビン類には、血球凝集素遺伝子の複製およびノイラミニダーゼ活性に対する阻害効果及びウイルス感染中に深刻な組織損傷やアポトーシスを引き起こす可能性がある炎症性サイトカインＩＬ－６の発現レベルを低下させる効果があるため、テアフラビン類はインフルエンザウイルスの複製阻害と抗炎症特性を持つ潜在的な化合物であることが示されている（非特許文献６）。 The fresh leaves of tea plant (Camellia sinensis) contain about 20% of polyphenol components such as catechins per dry weight, and "tea" (green tea, black tea, etc.) produced by processing the leaves and stems of tea plant. The extract of oolong tea, etc.) is a beverage containing abundant polyphenol components. Black tea contains polyphenols peculiar to black tea such as theaflavins, theacinencins, and thearubigin as catechin oxidation products in the production process of enzymatic oxidative fermentation. Among them, theaflavins have been found to have a direct effect on the infectivity of virus particles and are excellent in inactivating influenza virus in vitro (Non-Patent Document 5). In addition, theaflavins have the effect of inhibiting the replication and neurominidase activity of the hemagglutinin gene and the effect of reducing the expression level of the inflammatory cytokine IL-6, which can cause serious tissue damage and apoptosis during viral infection. Therefore, it has been shown that theaflabins are potential compounds having inhibition of influenza virus replication and anti-inflammatory properties (Non-Patent Document 6).
茶は世界中で最も一般的で、あらゆる社会において幅広い年齢層で飲用されている飲料である。また、茶は生産者である発展途上国の経済を支える重要な農作物でもある。世界では一日あたり３億杯の茶が摂取されており、この豊富な摂食経験は、茶ポリフェノールの安全性の根拠となる。さらに、これまでの臨床研究により、茶の摂取による様々な健康上の利点が示唆されている。例えば、抗酸化作用があるポリフェノールを豊富に含む茶の摂取は、心血管疾患のリスクを低下させる可能性があり（非特許文献７）、茶の習慣的な摂取は高齢者における健康関連のＱＯＬ向上に関連し、その関連性は緑茶よりも紅茶の方が高いことが示されている（非特許文献８）。 Tea is the most common beverage in the world and is consumed by a wide range of age groups in all societies. Tea is also an important crop that supports the economies of developing countries, which are producers. The world consumes 300 million cups of tea per day, and this abundant eating experience is the basis for the safety of tea polyphenols. In addition, previous clinical studies have suggested various health benefits from tea consumption. For example, ingestion of tea rich in antioxidant polyphenols may reduce the risk of cardiovascular disease (Non-Patent Document 7), and habitual ingestion of tea is a health-related QOL in the elderly. It has been shown that black tea is more relevant than green tea in relation to improvement (Non-Patent Document 8).
茶に含まれる成分について、急性上気道炎症の予防効果を検証した臨床研究の事例としては、高齢者を対象とした茶カテキン抽出物を用いたうがいによるインフルエンザの感染の抑制効果（非特許文献９）、茶カテキンおよびテアニンを封入したカプセル摂取によるインフルエンザ感染予防効果（非特許文献１０）、紅茶抽出液を用いたうがいによるインフルエンザ感染予防効果（非特許文献１１）が報告されている。 As an example of clinical research that verified the preventive effect of acute upper respiratory tract inflammation on the components contained in tea, the effect of suppressing influenza infection by gargling using the theanine extract for the elderly (Non-Patent Document 9). ), Influenza infection preventive effect by ingestion of capsules containing tea catechin and theanine (Non-Patent Document 10), and influenza infection preventive effect by gargling using tea extract (Non-Patent Document 11) have been reported.
上記のとおり、茶に含まれる成分について、急性上気道炎症の予防効果を検証した研究が開示されているが、これらは通常の茶の飲用習慣によるインフルエンザを含む急性上気道炎症の予防効果を検証したものではない。したがって本発明の目的は、通常の飲食条件において急性上気道炎症の発症および症状の抑制に対して有効な免疫増強剤を提供することにある。 As mentioned above, studies have disclosed studies verifying the preventive effect of acute upper respiratory tract inflammation on the components contained in tea, but these have verified the preventive effect of acute upper respiratory tract inflammation including influenza due to normal tea drinking habits. Not what I did. Therefore, an object of the present invention is to provide an immunopotentiator effective for suppressing the onset and symptoms of acute upper respiratory tract inflammation under normal eating and drinking conditions.
本発明者らは、上記課題を解決するために鋭意検討を重ねた過程で、紅茶ポリフェノールを含有するティーバッグの浸出液を１２週間継続して摂取した場合に、唾液中のＳＩｇＡとＮＫ細胞活性を上昇させることによって免疫を増強し、急性上気道炎症の発症リスクと症状の重症度を抑制しうることを発見し、本発明の完成に至った。 The present inventors have been diligently studying to solve the above-mentioned problems, and when the exudate of a tea bag containing black tea polyphenol is continuously ingested for 12 weeks, the SIgA and NK cell activity in saliva is increased. It was discovered that the increase in immunity can enhance immunity and suppress the risk of developing acute upper respiratory tract inflammation and the severity of symptoms, leading to the completion of the present invention.
すなわち、本発明は以下のとおりである。
［１］紅茶ポリフェノールを有効成分とする免疫増強剤。
［２］免疫が自然免疫および／または粘膜免疫である［１］に記載の免疫増強剤。
［３］急性上気道炎症状発現抑制用である［１］または［２］に記載の免疫増強剤。
［４］自然免疫増強の作用がＮＫ細胞活性を上昇させるもので、粘膜免疫増強の作用がＳＩｇＡを上昇させるものである［３］に記載の免疫増強剤。
［５］１バッグあたりに７０～１５０ｍｇのポリフェノールを含み、ポリフェノール中の８０％以上が紅茶ポリフェノールであることを特徴とする紅茶ティーバッグである［１］から［４］に記載の免疫増強剤。
［６］ポリフェノールとしてテアフラビン類および／またはテアシネンシン類をそれぞれ３．０ｍｇ以上含むものである［５］に記載の免疫増強剤。
。
［７］ヒトに対し、１２週間以上継続して１日あたり３バッグ分以上の紅茶浸出液を経口摂取 されるように用いられることを特徴とする［５］または［６］に記載の免疫増強剤。
That is, the present invention is as follows.
[1] An immunopotentiator containing black tea polyphenol as an active ingredient.
[2] The immunopotentiator according to [1], wherein the immunity is innate immunity and / or mucosal immunity.
[3] The immunopotentiator according to [1] or [2] for suppressing the onset of acute upper respiratory tract inflammation.
[4] The immuno-enhancing agent according to [3], wherein the action of enhancing innate immunity increases NK cell activity, and the action of enhancing mucosal immunity increases SIgA.
[5] The immunopotentiator according to [1] to [4], which is a black tea tea bag containing 70 to 150 mg of polyphenols per bag and having 80% or more of the polyphenols being black tea polyphenols.
[6] The immunopotentiator according to [5], which contains 3.0 mg or more of theaflavins and / or theacinencins as polyphenols, respectively.
..
[7] The immune enhancer according to [5] or [6], which is used so that humans can ingest 3 bags or more of black tea exudate per day continuously for 12 weeks or more. ..
本発明の紅茶ポリフェノールを有効成分として含有するティーバッグの浸出液（以下、この浸出液を「紅茶浸出液」または「紅茶」として表現する場合がある）を１２週間継続して摂取すると、ＳＩｇＡの上昇によって粘膜免疫を増強させ、また、ＮＫ細胞活性の上昇によって自然免疫を増強させるため、これらの作用によって急性上気道炎症の発症リスクと症状の重症化を抑制することができる。さらに、粘膜免疫に関しては、唾液中のＳＩｇＡ濃度が低いヒトに対しては分泌能力を向上させる作用を有する。したがって、本発明の紅茶を１２週間継続して日常的に摂取することは、免疫機能を強化し、急性上気道炎症などの外来抗原によるリスクを抑制するための食事療法となる。 When a tea bag exudate containing the black tea polyphenol of the present invention as an active ingredient (hereinafter, this exudate may be referred to as "black tea exudate" or "black tea") is continuously ingested for 12 weeks, the mucous membrane is increased due to an increase in SIgA. Since it enhances immunity and enhances innate immunity by increasing NK cell activity, these actions can suppress the risk of developing acute upper airway inflammation and the aggravation of symptoms. Furthermore, regarding mucosal immunity, it has an effect of improving the secretory capacity in humans with a low SIgA concentration in saliva. Therefore, daily intake of the black tea of the present invention for 12 weeks is a diet for strengthening the immune function and suppressing the risk of foreign antigens such as acute upper respiratory tract inflammation.
以下、本発明について詳細に説明する。なお、本明細書において、特別な記載がない場合、「％」は質量％を示す。また、「下限値～上限値」の数値範囲は、特に他の意味であることを明記しない限り、「下限値以上、上限値以下」の数値範囲を意味する。 Hereinafter, the present invention will be described in detail. In the present specification, unless otherwise specified, "%" indicates mass%. Further, the numerical range of "lower limit value to upper limit value" means a numerical range of "greater than or equal to the lower limit value and less than or equal to the upper limit value" unless otherwise specified.
本発明の免疫増強剤における有効成分は紅茶ポリフェノールである。紅茶ポリフェノールとは、チャノキ(Ｃａｍｅｌｌｉａ ｓｉｎｅｎｓｉｓ)の生葉などに存在するカテキン類（エピカテキン（ＥＣ）、エピカテキンガレート（ＥＣｇ）、エピガロカテキンガレート（ＥＧＣｇ）、ガロカテキン（ＧＣ）、カテキン（Ｃ）、ガロカテキンガレート（ＧＣｇ）およびカテキンガレート（Ｃｇ））が酸化酵素であるポリフェノールオキシダーゼの発酵作用によって酸化重合することで形成されたオリゴマー（テアシネンシン類、テアフラビン類等）や、さらに発酵が進むにつれこれら成分が複雑に重合した構造の定かではない化合物（テアルビジン類）を主とした紅茶に特有のポリフェノールを意味する。 The active ingredient in the immunopotentiator of the present invention is black tea polyphenol. Tea polyphenols are catechins (epigallocatechin (EC), epicatechin gallate (ECg), epigallocatechin gallate (EGCg), galocatechin (GC), catechin (C), etc., which are present in the fresh leaves of chanoki (Camellia sinensis). Oligomers (teacinensins, theaflavins, etc.) formed by oxidative polymerization of galocatechin gallate (GCg) and catechin gallate (Cg) by the fermentation action of polyphenol oxidase, which is an oxidase, and these components as fermentation progresses. Means a polyphenol peculiar to tea, mainly a compound (thealvidins) whose structure is uncertain, which is complicatedly polymerized.
本発明において紅茶ポリフェノール量とは、酒石酸鉄吸光光度法（参考文献１：文部科学省科学技術・学術政策局政策課資源室監修、「日本食品標準成分表２０１５年度版（七訂）分析マニュアル・解説」、建帛社２０１６年２月、ｐ．２４２－２４３）で測定されるポリフェノール量からＨＰＬＣ法で測定される総カテキン量（上記８種カテキン類の合計値）および没食子酸量を差し引いて求められるものである。 In the present invention, the amount of tea polyphenols is defined as the iron tartrate absorptiometry (Reference 1: Supervised by the Resources Office, Policy Division, Science and Technology Policy Bureau, Ministry of Education, Culture, Sports, Science and Technology, "Japanese Food Standard Ingredients Table 2015 Edition (7th Edition) Analysis Manual". Explanation ”, Kenjosha, February 2016, p.242-243) minus the total amount of catechins measured by the HPLC method (total value of the above 8 types of catechins) and the amount of gallic acid. It is something that can be done.
本発明においてテアフラビン類とは、上記カテキン類の２分子が重合し、分子内にベンゾトロポロン環を有する２量体のカテキン重合物であり、テアフラビン１（テアフラビン）、テアフラビン２Ａ(テアフラビン－３－ガレート)、テアフラビン２Ｂ（テアフラビン－３’－ガレート）、テアフラビン３（テアフラビン－３，３’－ジガレート）の４種を意味する。これらはＨＰＬＣ法によって定量することができ、前記４種のテアフラビンの合算値をテアフラビン類量とする。 In the present invention, theaflavins are dimeric catechin polymers having two molecules of the above catechins polymerized and having a benzotroporone ring in the molecules, and are theaflavin 1 (theaflavin) and theaflavin 2A (theaflavin-3-gallate). ), Theaflavin 2B (theaflavin-3'-gallate), theaflavin 3 (theaflavin-3,3'-jigallate). These can be quantified by the HPLC method, and the total value of the above four kinds of theaflavins is used as the theaflavin amount.
本発明においてテアシネンシン類とは、上記カテキン類のうちでピロガロール構造を有するカテキン２分子が重合した２量体のカテキン重合物であり、その構成と立体構造によりテアシネンシンＡ～Ｇが知られているが、本発明においては主要なテアシネンシンであるテアシネンシンＡ～Ｃの３種を意味する。これらはＨＰＬＣ法によって定量することができ、３種テアシネンシンの合算値をテアシネンシン類量とする。 In the present invention, the catechins are dimer catechin polymers obtained by polymerizing two catechin molecules having a pyrogallol structure among the above catechins, and the catechins A to G are known due to their composition and three-dimensional structure. In the present invention, it means three kinds of techinencins A to C, which are the main techinencins. These can be quantified by the HPLC method, and the total value of the three kinds of theacinencin is used as the amount of theacinencin.
上記の紅茶ポリフェノールは免疫増強剤として機能する。これらは紅茶葉中に含まれるものであり、本発明においては紅茶葉を水や熱水を用いて有効成分を浸出させた液を継続して摂取することで免疫増強作用を享受することができる。ここで、紅茶葉の浸出方法としては、紅茶葉をティーポットに入れて熱水を注ぎ、茶漉しにより茶葉を取り除く方法でも良いが、紅茶葉を不織布などのメッシュ状の素材に封入したいわゆるティーバッグの形態から浸出するのが好ましい。ティーバッグの形態では一定量の茶葉が封入されていることから、有効成分である紅茶ポリフェノールを安定して簡便に取り出すことができるため、日常的に継続して摂取するのに適している。茶葉やティーバッグを浸出する際の水は常温以下の低温水から沸騰直後の熱水まで利用可能であるが、紅茶ポリフェノールの浸出特性から高温の水で浸出させるのが有効である。本発明では、上記のように紅茶葉から成分が浸出された状態の液体を「紅茶浸出液」または単に「紅茶」として扱う。 The above black tea polyphenols function as immunopotentiators. These are contained in black tea leaves, and in the present invention, the immune enhancing effect can be enjoyed by continuously ingesting a liquid in which the active ingredient is exuded from the black tea leaves using water or hot water. .. Here, as a method of leaching the black tea leaves, a method of putting the black tea leaves in a teapot, pouring hot water into them, and removing the black tea leaves by a tea strainer may be used, but a so-called tea bag in which the black tea leaves are enclosed in a mesh-like material such as a non-woven fabric. It is preferable to exude from the form of. Since a certain amount of tea leaves are enclosed in the form of a tea bag, the active ingredient, black tea polyphenol, can be stably and easily taken out, and is suitable for continuous ingestion on a daily basis. Water for leaching tea leaves and tea bags can be used from low-temperature water below room temperature to hot water immediately after boiling, but it is effective to leaching with high-temperature water due to the leaching characteristics of black tea polyphenols. In the present invention, the liquid in which the components are exuded from the black tea leaves as described above is treated as "black tea leachate" or simply "black tea".
ティーバッグの中にはポリフェノールを７０～１５０ｍｇを含有する茶葉が封入されているのが好ましく、浸出液の香味との関係から、その茶葉量は紅茶一杯分（およそ１５０ｍｌ）に対して１．０～３．０ｇであるのが一般的で、１．５～２．５ｇであるのが好ましい。また、茶葉中のポリフェノール含有率は５～３５％が好ましく。１０～２５％がより好ましい。また、ポリフェノールに占める紅茶ポリフェノールの含有率は８０％以上であることが好ましい。このような茶葉を利用することによって、本発明の効果を安定的に享受することができる。また、紅茶ポリフェノールの中でもテアフラビン類とテアシネンシン類は特に効果が期待できる成分であり、これらは紅茶一杯分の茶葉の中にいずれも３．０ｍｇ以上を含有するのが好ましく、茶葉あたりでは０．１～５．０％が好ましい。その他、あらかじめ紅茶葉から抽出した紅茶抽出物をティーバッグの中に封入し、紅茶ポリフェノール分を強化しても良い。） It is preferable that tea bags containing 70 to 150 mg of polyphenols are enclosed in the tea bag, and the amount of tea leaves is 1.0 to 1.0 to one cup of black tea (about 150 ml) in relation to the flavor of the leachate. It is generally 3.0 g, preferably 1.5 to 2.5 g. The polyphenol content in tea leaves is preferably 5 to 35%. 10 to 25% is more preferable. Further, the content of black tea polyphenol in the polyphenol is preferably 80% or more. By using such tea leaves, the effects of the present invention can be stably enjoyed. Among black tea polyphenols, theaflavins and theacinencins are components that can be expected to be particularly effective, and it is preferable that each of these is contained in the tea leaves of a cup of black tea in an amount of 3.0 mg or more, and 0.1 per tea leaf. ~ 5.0% is preferable. In addition, a black tea extract previously extracted from black tea leaves may be enclosed in a tea bag to enhance the black tea polyphenol content. )
本発明において、「免疫増強」とは、ヒトまたは動物の免疫機能を高める作用または低下した機能を回復するなどの免疫調節作用を意味し、本発明の免疫増強剤は「自然免疫」と「粘膜免疫」を増強させ、その結果として急性上気道炎症のような感染症等の各種疾患の予防治療改善効果を期待することができる。 In the present invention, "immunity enhancing" means an immunomodulatory action such as an action of enhancing or restoring the immune function of a human or an animal, and the immunopotentiating agent of the present invention is "spontaneous immunity" and "mucosal membrane". "Immune" can be enhanced, and as a result, the effect of preventing and improving various diseases such as infectious diseases such as acute upper airway inflammation can be expected.
自然免疫とは、生体が備える免疫のうち、生体に先天的に備わっており、事前に抗原に暴露していなくても前記抗原を生体から排除するに際に機能する機構を意味する。本発明における自然免疫の増強剤としてより具体的には、ナチュラルキラー細胞（Ｎａｔｕｒａｌ Ｋｉｌｌｅｒ Ｃｅｌｌ：ＮＫ細胞）等を介した非特異的な免疫応答を活性化する薬剤を意味する。なお、ＮＫ細胞の活性は５１Ｃｒ遊離法により定量することができる。ＮＫ細胞はリンパ球の一つであり、癌細胞やウイルス性疾患に対する主要な防御メカニズムとして機能する重要な自然免疫細胞であり、事前の感作なしに腫瘍細胞やウイルス感染細胞を攻撃することができる。本発明では、全身免疫系へ影響する血清中のＮＫ細胞の細胞傷害活性を対象とする。ＮＫ細胞活性と急性上気道炎症との関連性については、健常人が風邪に罹る頻度はＮＫ活性およびＮＫサブセット（ＣＤ３－ＣＤ１６＋ＣＤ５６＋）の割合と逆相関していることが報告されている（参考文献２：Environmental Health and Preventive Medicine（2000），4(4)，p.212-216)。また、ＮＫ細胞活性と感染症発症との関連性については、高齢者における低ＮＫ細胞活性が感染症の発症と短生存率と相関していることが報告されている（参考文献３：Clinical & Experimental Immunology（2001），124(3)，p.392-397）。 Innate immunity means a mechanism that is innately provided in a living body and functions in eliminating the antigen from the living body even if it is not exposed to the antigen in advance. More specifically, as the innate immunity enhancer in the present invention, it means an agent that activates a non-specific immune response via natural killer cells (NK cells) and the like. The activity of NK cells can be quantified by the 51 Cr release method. NK cells are one of the lymphocytes, important natural immune cells that function as the main defense mechanism against cancer cells and viral diseases, and can attack tumor cells and virus-infected cells without prior sensitization. can. The present invention targets the cytotoxic activity of NK cells in serum that affects the systemic immune system. Regarding the association between NK cell activity and acute upper respiratory tract inflammation, it has been reported that the frequency of colds in healthy individuals is inversely correlated with the proportion of NK activity and NK subset (CD3-CD16 + CD56 +) (references). 2: Environmental Health and Preventive Medicine (2000), 4 (4), p.212-216). Regarding the relationship between NK cell activity and the onset of infectious diseases, it has been reported that low NK cell activity in the elderly correlates with the onset of infectious diseases and short survival rate (Reference 3: Clinical &). Experimental Immunology (2001), 124 (3), p.392-397).
粘膜免疫とは、ウイルスや病原性微生物の侵入口である粘膜面で機能する免疫であり、二量体の分泌型免疫グロブリンA（Ｓｅｃｒｅｔｏｒｙ Ｉｍｍｕｎｏｇｌｏｂｕｌｉｎ Ａ：ＳＩｇＡ）は上気道および消化管の粘膜上皮から分泌される粘液に含まれる主要な粘膜免疫成分であり、最初の生体防御線として機能する。粘液に外来抗原および病原性微生物を閉じ込め、上皮受容体へのアクセスを阻害し、付着および中和によってそれらを不活性化し、蠕動および粘液線毛活動による除去を容易にする。ＳＩｇＡは抗体の可変領域とは無関係に、上皮表面への病原体と毒素の付着を防ぐこともでき、自然免疫系の構成要素と見なすこともできる。呼吸器と消化管の入り口として重要な役割を果たしている口腔内には唾液SＩｇＡが多量に存在しており、一日に約５０～２００ｍｇが分泌されている。本発明における粘膜免疫の増強剤とは具体的には、口腔内のＳＩｇＡ量の増加による粘膜免疫を増強する薬剤を意味する。なお、唾液中のＳＩｇＡは競合ＥＬＩSＡ法により定量することができる。 Mucosal immunity is the immunity that functions on the mucosal surface, which is the entry point for viruses and pathogenic microorganisms, and the secretory immunoglobulin A (SIgA) of the dimer is from the mucosal epithelium of the upper airway and gastrointestinal tract. It is the main mucosal immune component contained in the secreted mucous membrane and functions as the first line of defense. It traps foreign antigens and pathogenic microorganisms in the mucus, blocks access to epithelial receptors, inactivates them by attachment and neutralization, and facilitates removal by peristaltic and mucous ciliary activity. SIgA can also prevent the attachment of pathogens and toxins to the epithelial surface, independent of the variable region of the antibody, and can be considered a component of the innate immune system. A large amount of saliva SIgA is present in the oral cavity, which plays an important role as an entrance to the respiratory tract and the digestive tract, and about 50 to 200 mg is secreted daily. Specifically, the mucosal immunity enhancer in the present invention means an agent that enhances mucosal immunity by increasing the amount of SIgA in the oral cavity. SIgA in saliva can be quantified by the competitive ELISA method.
本発明の免疫増強剤のヒトへの投与方法は、上記のとおり茶葉をティーバッグの形態などから浸出させて得られる紅茶浸出液を経口摂取するものである。紅茶浸出液の投与量は上記ティーバッグとして１日あたり３バッグ分以上であることが好ましい。また、投与の期間は継続して１２週間以上であることが好ましい。本発明の免疫増強剤の有効成分である紅茶ポリフェノールを含むティーバッグの浸出液を１日あたり３バッグ分以上を継続して１２週間以上経口摂取した場合に、ＳＩｇＡの上昇によって粘膜免疫を増強させ、また、ＮＫ細胞活性の上昇によって自然免疫を増強させるため、これらの作用によって急性上気道炎症の発症リスクと症状の重症度を抑制することができる。さらに、粘膜免疫では、唾液中のＳＩｇＡ濃度が低いヒトでは分泌能力を向上させる。したがって、本発明の紅茶を１２週間継続して摂取することは、免疫機能を強化し、急性上気道炎症などの外来抗原によるリスクを抑制するための食事療法となる。 The method for administering the immunopotentiator of the present invention to humans is to orally ingest a black tea leachate obtained by exuding tea leaves from the form of a tea bag or the like as described above. The dose of black tea leachate is preferably 3 bags or more per day as the tea bag. In addition, the administration period is preferably 12 weeks or longer continuously. When the exudate of a tea bag containing tea polyphenol, which is the active ingredient of the immune enhancer of the present invention, is orally ingested for 12 weeks or more continuously for 3 bags or more per day, the increase in SIgA enhances mucosal immunity. In addition, since innate immunity is enhanced by increasing NK cell activity, the risk of developing acute upper airway inflammation and the severity of symptoms can be suppressed by these actions. In addition, mucosal immunity improves secretory capacity in humans with low SIgA levels in saliva. Therefore, continuous ingestion of the black tea of the present invention for 12 weeks is a diet therapy for strengthening the immune function and suppressing the risk of foreign antigens such as acute upper respiratory tract inflammation.
以下に本発明を実施例によってさらに具体的に説明するが、本発明は実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to the examples.
本発明の紅茶ポリフェノールを有効成分とする免疫増強剤の摂取による急性上気道炎症に対する抑制効果をプラセボと比較するため、ランダム化プラセボ対照単盲検並行群間比較試験を実施した。インフォームドコンセントを得た２０～５９才の成人被験候補者に対し、ベースラインを評価するため、自己調査票（年齢、性別、ＢＭＩ、喫煙とアルコール摂取習慣、インフルエンザウイルスのワクチン接種など）に回答し、身体測定、血圧、血液学検査、血液生化学検査、尿検査、インフルエンザ抗体価（Ａ型：Ｈ１Ｎ１およびＨ３Ｎ２、Ｂ型：山形系統およびビクトリア系統）、ＮＫ細胞活性（Ｅ／Ｔ比１０：１および２０：１）、唾液ＳＩｇＡの事前検査を受けさせ、以下の基準で被験者の適格性を判断した。 In order to compare the inhibitory effect of the intake of the black tea polyphenol-containing immunopotentiator of the present invention on acute upper respiratory tract inflammation with placebo, a randomized placebo-controlled, single-blind, parallel-group comparative study was conducted. Answer self-questionnaire (age, gender, BMI, smoking and alcohol intake habits, influenza virus vaccination, etc.) to assess baselines for adult test candidates aged 20-59 years with informed outlets However, anthropometry, blood pressure, hematology test, blood biochemical test, urine test, influenza antibody titer (A type: H1N1 and H3N2, B type: Yamagata strain and Victoria strain), NK cell activity (E / T ratio 10: 1 and 20: 1), the subject was subjected to a pre-examination of saliva SIgA, and the eligibility of the subject was judged according to the following criteria.
＜適格性基準＞
（I）同意取得時の年齢が２０歳以上６０歳未満の健常者。
（II）当該試験について十分な説明を受け、内容を理解することができ、本人による文書同意が得られる者。
＜除外基準＞
（i）同意取得日より起算して８カ月前から試験開始２４時間前までにインフルエンザに罹患した者。
（ii）同意取得日から起算して８カ月以内にインフルエンザワクチンを接種した者。
（iii）特定保健用食品、機能性表示食品、健康食品を常用しており、試験期間中に中止できない者。
（iv）茶類（緑茶、ウーロン茶、紅茶、麦茶など）に対するアレルギーを有する者。
（v）茶飲料を一日あたり２Ｌ以上飲む習慣のある者。
（vi）心臓、肝臓、腎臓、呼吸器、消化器に重篤な現病歴、既往歴がある者。
（vii）妊娠中、試験期間中に妊娠予定・意志のある者、授乳中の者。
（viii）他の医薬品または健康食品の臨床試験に参加中、試験終了後４週間以内、あるいは当該試験の参加同意後に他の臨床試験に参加する予定のある者。
（ix）同意取得日から１ヶ月以内に、成分献血あるいは全血２００ｍＬ献血を行った者。
（x）同意取得日から３ヶ月以内に、全血４００ｍＬ献血を行った男性。
（xi）同意取得日から４ヶ月以内に、全血４００ｍＬ献血を行った女性。
（xii）同意取得日から１２ヶ月以内の採血量に、当該試験の予定総採血量を加えると１２００ｍＬを超える男性。
（xiii）同意取得日から１２ヶ月以内の採血量に、当該試験の予定総採血量を加えると８００ｍＬを超える女性。
（xiv）試験責任医師または試験分担医師が本試験への参加が不適当と判断した者。
<Eligibility criteria>
(I) A healthy person whose age at the time of obtaining consent is 20 to 60 years old.
(II) A person who has received sufficient explanation about the test, can understand the contents, and can obtain the written consent of the person.
<Exclusion criteria>
(I) Those who suffered from influenza from 8 months before the start of the study to 24 hours before the start of the study, counting from the date of consent acquisition.
(Ii) Those who have been vaccinated with influenza vaccine within 8 months from the date of consent acquisition.
(Iii) Persons who regularly use foods for specified health use, foods with functional claims, and health foods and cannot discontinue during the test period.
(Iv) Those who have allergies to teas (green tea, oolong tea, black tea, barley tea, etc.).
(V) Those who have a habit of drinking 2L or more of tea beverages per day.
(Vi) Those who have a serious current medical history or medical history of the heart, liver, kidneys, respiratory organs, and digestive organs.
(Vii) Those who are pregnant, willing to become pregnant during the test period, or breastfeeding.
(Viii) Those who are participating in a clinical trial of another drug or health food, and who plan to participate in another clinical trial within 4 weeks after the end of the trial or after consenting to participate in the trial.
(Ix) Those who donated blood components or 200 mL of whole blood within one month from the date of consent acquisition.
(X) A man who donated 400 mL of whole blood within 3 months from the date of consent acquisition.
(Xi) A woman who donated 400 mL of whole blood within 4 months from the date of consent acquisition.
(Xii) Males exceeding 1200 mL when the planned total blood sampling volume of the study is added to the blood sampling volume within 12 months from the date of consent acquisition.
(Xiii) Women who collected more than 800 mL when the planned total blood sampling volume of the study was added to the blood sampling volume within 12 months from the date of consent acquisition.
(Xiv) A person who is deemed inappropriate to participate in this study by the investigator or the investigator.
試験責任医師によって適格性基準を満たし、試験への参加に問題が無いと判断した者のうち、インフルエンザ抗体価が低いこと（Ａ型／Ｈ１Ｎ１）を第一優先とし、ＮＫ細胞活性（Ｅ／Ｔ比１０：１）が低いことを第二優先として、７２名の被験者を選定した。試験品作成者は、外観形状が同一となるように作成した2種のティーバッグ（紅茶：被験品（本発明品）、麦茶：比較品）とし、各々に異なる試験品記号を無作為に割り当てた。割付責任者は、選定された７２名の被験者に被験者コードを付し、性別、年齢、インフルエンザ抗体価（Ａ型／Ｈ１Ｎ１およびＡ型／Ｈ３Ｎ２）、ＮＫ細胞活性（Ｅ／Ｔ比１０：１）、唾液ＳＩｇＡ濃度および被験者選定時までのインフルエンザワクチン接種者数について考慮して３６名ずつの２群（本発明の紅茶摂取群：被験群、麦茶摂取群：比較群）に層別割付を行い、各群に異なる試験群記号を付した。なお、層別因子において試験群間で大きく偏らないように考慮した。被験者コード、試験群記号および試験品記号を紐づけた割付け表は割付責任者によって厳重に保管し、試験実施者、試験責任医師および試験分担医師への開示はデータ固定まで行わなかった。 Among those who meet the eligibility criteria and judge that there is no problem in participating in the study by the investigator, the first priority is low influenza antibody titer (type A / H1N1), and NK cell activity (E / T). Seventy-two subjects were selected with the second priority being a low ratio of 10: 1). The test product creator made two types of tea bags (black tea: test product (invention product), barley tea: comparative product) created so that the appearance and shape are the same, and randomly assigned different test product symbols to each. rice field. The person in charge of allocation attached the subject code to the 72 selected subjects, and the sex, age, influenza antibody titer (type A / H1N1 and type A / H3N2), and NK cell activity (E / T ratio 10: 1). , Saliva SIgA concentration and the number of influenza vaccinated persons up to the time of subject selection were taken into consideration, and two groups of 36 persons (tea intake group: test group, wheat tea intake group: comparison group of the present invention) were stratified. Each group was given a different test group symbol. Consideration was given so that the stratification factors were not significantly biased among the test groups. The assignment table linked with the subject code, test group symbol, and test product symbol was kept strictly by the assigner, and was not disclosed to the tester, the investigator, and the investigator until the data was fixed.
被験者には、１日に３杯の試験品（被験品：紅茶、比較品：麦茶）を１２週間（８４日間）摂取させた。試験品は内容量をそれぞれ紅茶２．０ｇ、麦茶１．５ｇのティーバッグの形態とし、いずれの試験品も白色無地の外装で個包装したものを用いた。試験品の摂取方法としては、ティーバッグ１つを１５０ｍＬの沸騰水で９０秒間浸漬して得られる浸出液約１３０ｍＬを１杯分とし、被験者には試験品には砂糖やミルク等の他の食品素材は加えず、そのまま摂取するよう求めた。なお、紅茶ティーバッグの内容物については市販のティーバッグ商品「日東デイリークラブ（三井農林製）」と同じものを採用した。 The subjects were allowed to ingest 3 cups of the test product (test product: black tea, comparative product: barley tea) daily for 12 weeks (84 days). The test products were in the form of tea bags with contents of 2.0 g of black tea and 1.5 g of barley tea, respectively, and both test products were individually wrapped with a plain white exterior. As a method of ingesting the test product, one tea bag is immersed in 150 mL of boiling water for 90 seconds, and about 130 mL of the exudate obtained is used as one cup. Was not added and was requested to be taken as it is. The contents of the tea bag are the same as those of the commercially available tea bag product "Nitto Daily Club (manufactured by Mitsui Norin)".
試験品の詳細を表１に示した。試験品中の成分含量は以下の方法により測定した。
・総ポリフェノール量：酒石酸鉄吸光光度法により測定した（参考文献４：文部科学省科学技術・学術政策局政策課資源室監修、「日本食品標準成分表２０１５年度版（七訂）分析マニュアル・解説」、建帛社２０１６年２月、p.２４２－２４３）。
・カテキン類、カフェイン：ＨＰＬＣ法により測定した（参考文献５：特開２０１８－１３４０５２号公報）。総カテキン量は、エピカテキン（ＥＣ）、エピカテキンガレート（ＥＣｇ）、エピガロカテキンガレート（ＥＧＣｇ）、ガロカテキン（ＧＣ）、カテキン（Ｃ）、ガロカテキンガレート（ＧＣｇ）およびカテキンガレート（Ｃｇ）含量の合算値とした。
・テアフラビン類：ＨＰＬＣ法により測定した（参考文献６：特開２０１０－３５５４８号公報）。総テアフラビン量は、ＴＦ１、ＴＦ２Ａ、ＴＦ２ＢおよびＴＦ３含量の合算値とした。
・テアシネンシン類：ＨＰＬＣ法により測定した（参考文献７：特開２０１０－１３８１０３号公報）。総テアシネンシン量は、テアシネンシンＡ、テアシネンシンＢおよびテアシネンシンＣ含量の合算値とした。
・紅茶ポリフェノール：総ポリフェノール量から総カテキン量および没食子酸量を差し引いた値を紅茶ポリフェノール量とした。
Details of the test product are shown in Table 1. The component content in the test product was measured by the following method.
・ Total amount of polyphenol: Measured by absorptiometry of iron tartrate (Reference 4: Supervised by Resources Office, Policy Division, Science and Technology Policy Bureau, Ministry of Education, Culture, Sports, Science and Technology, "Standard Tables of Food Composition in Japan 2015 (7th revision) Analysis Manual / Explanation" , Kenjosha, February 2016, p.242-243).
-Catechins, caffeine: Measured by HPLC method (Reference 5: Japanese Unexamined Patent Publication No. 2018-134052). The total amount of catechin is the content of epicatechin (EC), epicatechin gallate (ECg), epigallocatechin gallate (EGCg), gallocatechin (GC), catechin (C), gallocatechin gallate (GCg) and catechin gallate (Cg). It was the total value.
Theaflavins: Measured by HPLC method (Reference 6: JP-A-2010-35548). The total amount of theaflavin was the sum of the contents of TF1, TF2A, TF2B and TF3.
-Teacinencins: Measured by HPLC method (Reference 7: JP-A-2010-138103). The total amount of teasinencin was the sum of the contents of teasinencin A, teasinencin B and teasinencin C.
-Black tea polyphenols: The value obtained by subtracting the total amount of catechins and the amount of gallic acid from the total amount of polyphenols was defined as the amount of black tea polyphenols.
表１に示した分析結果より、被験群の被験者は、試験品から１日あたり約２７０±３１ｍｇの総ポリフェノール（うち、２６．５±０．１ｍｇのカテキン類、１２．８±０．３ｍｇのテアフラビン類、１７．２±０．２ｍｇのテアシネンシン類、１０．４±０．１ｍｇの没食子酸を含む）および１０４．５±１．８ｍｇのカフェインを摂取したことが確認される。なお、紅茶ポリフェノールは総ポリフェノール中の約８８．１％を占めていた。 From the analysis results shown in Table 1, the subjects in the test group were about 270 ± 31 mg of total polyphenols per day from the test product (of which 26.5 ± 0.1 mg of catechins and 12.8 ± 0.3 mg). It is confirmed that theaflavins, 17.2 ± 0.2 mg of theacinencins, 10.4 ± 0.1 mg of gallic acid) and 104.5 ± 1.8 mg of caffeine were ingested. Black tea polyphenols accounted for about 88.1% of the total polyphenols.
＜有効性評価＞
有効性評価における主要評価項目として、試験品摂取期間中に発生した、急性上気道炎症状の発現率、インフルエンザ罹患（臨床診断あり）の発現率、急性上気道炎症状の発現回数、急性上気道炎症状発現１回当たりの罹患期間、試験品の摂取開始から急性上気道炎症の発現およびインフルエンザ罹患までの日数について評価した。また、副次評価項目として、ＷＵＲＳＳ－２１調査票、唾液中ＳＩｇＡ濃度変化、ＮＫ細胞活性の変化およびインフルエンザ抗体価の変化について評価した。各々の検査方法を以下に示す。
<Effectiveness evaluation>
The primary endpoints in efficacy evaluation are the incidence of acute upper respiratory tract inflammatory symptoms, the incidence of influenza (with clinical diagnosis), the frequency of acute upper respiratory tract inflammatory symptoms, and the acute upper respiratory tract during the test product intake period. The duration of illness per onset of inflammatory symptoms, the number of days from the start of ingestion of the test product to the onset of acute upper respiratory tract inflammation and the onset of influenza were evaluated. In addition, as secondary endpoints, the WURSS-21 questionnaire, changes in saliva SIgA concentration, changes in NK cell activity, and changes in influenza antibody titer were evaluated. Each inspection method is shown below.
（１）自覚症状
試験品の摂取期間中、被験者は日誌に試験品の摂取、食事、飲酒、試験品以外の茶飲料の摂取、体温、自覚症状、医療機関の受診・治療に関する事項、およびＷＵＲＳＳ－２１調査票（参考文献８：Health and Quality of Life(2009)，7(76)）日本語版に毎日の状況を記録させた。ＷＵＲＳＳ－２１調査票では、急性上気道炎症に共通する１０項目の症状と、ＱＯＬに対する９項目の機能障害に関して、０（障害がない、又は全くない）から１点（非常に軽度）、３点（軽度）、５点（中程度）、７点（重度）までの８ポイントのリッカート尺度でスコアリングした。
(1) Subjective symptom During the intake period of the test product, the subject kept in the diary the test product intake, meal, drinking, ingestion of tea beverages other than the test product, body temperature, subjective symptoms, matters related to medical institution consultation / treatment, and WURSS. -21 Questionnaire (Reference 8: Health and Quality of Life (2009), 7 (76)) The Japanese version was made to record the daily situation. According to the WURSS-21 questionnaire, 10 items of symptoms common to acute upper respiratory tract inflammation and 9 items of dysfunction for quality of life are 0 (no or no disorder) to 1 point (very mild) and 3 points. Scored on an 8-point Likert scale of up to (mild), 5 (moderate), and 7 (severe).
（２）唾液ＳＩｇＡ濃度
事前検査時および摂取終了時（１２週間）に検査を行った。食後３０分以上経過後、うがい後の安静時に流涎法により２～３ｍＬ程度の唾液を採取し、凍結保管をした。この唾液についてＳａｌｉｖａｒｙ Ｓｅｃｒｅｔｏｒｙ ＩｇＡ ｉｎｄｉｒｅｃｔ ｅｎｚｙｍｅ ｉｍｍｕｎｏａｓｓａｙ ｋｉｔ（Ｓａｌｉｍｅｔｒｉｃｓ， ＬＬＣ．）を用い、競合ＥＬＩSＡ法により唾液中のSＩｇＡ濃度を定量した。
(2) Saliva SIgA concentration The test was performed at the time of the preliminary test and at the end of intake (12 weeks). After 30 minutes or more after eating, about 2 to 3 mL of saliva was collected by the saliva method at rest after gargling, and stored frozen. For this saliva, the SIgA concentration in saliva was quantified by a competitive ELISA method using a Salivary Secretory IgA immunoassay kit (Salimetrics, LLC.).
（３）ＮＫ細胞活性
事前検査時および摂取終了時（１２週間）に検査を行った。被験者の末梢血から比重遠心分離法により回収したリンパ球を効果細胞（エフェクター細胞）とし、５１Ｃｒ標識したＫ５６２細胞をＮＫ細胞感受性細胞（標識細胞）として共培養した。リンパ球の細胞傷害作用により遊離した５１Ｃｒの放射性活性を測定し、ＮＫ細胞活性（％）を以下の計算式に基づき算出した。ＮＫ細胞活性（％）＝（細胞遊離値ｃｐｍ－自然遊離値ｃｐｍ）／（最大遊離値ｃｐｍ－自然遊離値ｃｐｍ）×１００とした。Ｅｆｆｅｃｔｅｒ ｃｅｌｌ／Ｔａｒｇｅｔ ｃｅｌｌ（Ｅ／Ｔ比）は１０：１および２０：１とした場合の２条件でＮＫ細胞活性を求めた。
(3) NK cell activity The test was performed at the time of the preliminary test and at the end of ingestion (12 weeks). Lymphocytes collected from the peripheral blood of the subject by specific gravity centrifugation were used as effect cells (effector cells), and 51 Cr-labeled K562 cells were co-cultured as NK cell-sensitive cells (labeled cells). The radioactive activity of 51 Cr released by the cytotoxic action of lymphocytes was measured, and the NK cell activity (%) was calculated based on the following formula. NK cell activity (%) = (cell free value cpm-natural free value cpm) / (maximum free value cpm-natural free value cpm) × 100. The NK cell activity was determined under two conditions when the Effector cell / Target cell (E / T ratio) was 10: 1 and 20: 1.
（４）インフルエンザウイルス抗体価
事前検査時および摂取終了時（１２週間）に検査を行った。２０１９／２０２０シーズンのインフルエンザＨＡワクチン製造株をウイルス抗原（Ａ／Ｂｒｉｓｂａｎｅ／０２／２０１８（Ｈ１Ｎ１）ｐｄｍ０９、Ａ／Ｋａｎｓａｓ／１４／２０１７（Ｈ３Ｎ２）、Ｂ／Ｐｈｕｋｅｔ／３０７３／２０１３（山形系統）、Ｂ／Ｍａｒｙｌａｎｄ／１５／２０１６（ビクトリア系統））として赤血球凝集阻止反応試験によりインフルエンザウイルス抗体価を測定した。
(4) Influenza virus antibody titer The test was performed at the time of pre-test and at the end of ingestion (12 weeks). Influenza HA vaccine production strains for the 2019/2020 season were used as virus antigens (A / Brisbane / 02/2018 (H1N1) pdm09, A / Kansas / 14/2017 (H3N2), B / Phuket / 3073/2013 (Yamagata strain), B. Influenza virus antibody titer was measured by hemagglutination inhibition reaction test as / Maryland / 15/2016 (Victoria strain).
＜安全性評価項目＞
安全性評価項目として、試験品の摂取開始から摂取終了後4週間後までの試験期間中に発生した有害事象および副作用の発現率について評価した。
<Safety evaluation items>
As safety endpoints, the incidence of adverse events and side effects that occurred during the test period from the start of ingestion of the test product to 4 weeks after the end of ingestion was evaluated.
＜その他評価項目＞
事前検査時、摂取開始後６週間、終了時（１２週間）および終了後４週間（１６週目）に身長、体重を測定してＢＭＩを算出した。また、生理学検査として収縮期血圧、拡張期血圧、脈拍数を測定した。また、血液学検査として白血球数（ＷＢＣ）、赤血球数（ＲＢＣ）、ヘモグロビン（Ｈｂ）、ヘマトクリット（Ｈｔ）、血小板数（ＰＬＴ）、血液生化学検査として総蛋白質（ＴＰ）、アルブミン（ＡＬＢ）、ａｓｐａｒｔａｔｅ ａｍｉｎｏｔｒａｎｓｆｅｒａｓｅ（ＡＳＴ）、ａｌａｎｉｎｅ ａｍｉｎｏｔｒａｎｓｆｅｒａｓｅ（ＡＬＴ）、乳酸脱水素酵素（ＬＤＨ）、総ビリルビン（Ｔ－ＢＩＬ）、アルカリホスファターゼ（ＡＬＰ）、γ－グルタミルトランスペプチダーゼ（γ－ＧＴＰ）、クレアチンキナーゼ（ＣＰＫ）、尿素窒素（ＢＵＮ）、クレアチニン（ＣＲＥ）、尿酸（ＵＡ）、ナトリウム（Ｎａ）、クロール（Ｃｌ）、カリウム（Ｋ）、カルシウム（Ｃａ）、総コレステロール（Ｔ－Ｃｈｏ）、ｌｏｗ ｄｅｎｓｉｔｙ ｌｉｐｏｐｒｏｔｅｉｎ－コレステロール（ＬＤＬ－Ｃｈｏ）、ｈｉｇｈ ｄｅｎｓｉｔｙ ｌｉｐｏｐｒｏｔｅｉｎ－コレステロール（ＨＤＬ－Ｃｈｏ）、中性脂肪（ＴＧ）、血糖（ＧＬＣ）、ヘモグロビンＡｌｃ（ＨｂＡ１ｃ）および尿検査（蛋白定性、糖定性、ウロビリノーゲン、ビリルビン）を測定した。
<Other evaluation items>
BMI was calculated by measuring height and weight at the time of pre-examination, 6 weeks after the start of intake, at the end (12 weeks) and 4 weeks (16th week) after the end of intake. In addition, systolic blood pressure, diastolic blood pressure, and pulse rate were measured as physiological tests. In addition, as a hematological test, leukocyte count (WBC), erythrocyte count (RBC), hemoglobin (Hb), hematocrit (Ht), platelet count (PLT), and as a blood biochemical test, total protein (TP), albumin (ALB), aspartate aminotransphase (AST), albumin aminotransphase (ALT), lactic acid dehydrogenase (LDH), total bilirubin (T-BIL), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GTP), creatin kinase (CPK) , Urea nitrogen (BUN), creatinine (CRE), uric acid (UA), sodium (Na), chlor (Cl), potassium (K), calcium (Ca), total cholesterol (T-Cho), low density lipoprotein-cholesterol (LDL-Cho), high density lipoprotein-cholesterol (HDL-Cho), neutral fat (TG), blood glucose (GLC), hemoglobin Alc (HbA1c) and urine test (protein qualitative, glycolytic, urobilinogen, bilirubin) did.
＜統計解析＞
サンプルサイズの設計に際しては、カテキン飲料による急性上気道炎症の抑制効果に関する過去の研究（参考文献９：Nutrients(2019），12(１);４）、ＮＫ活性と感冒頻度の関係（参考文献１０：Environmental Health and Preventive Medicine(2000)，4(4)，p. 212-216）、紅茶の消費量とインフルエンザの発生率の内部調査結果（データ非開示）を参考にした。急性上気道炎症の発生率は被験群で２７．０％、比較群で６４．８％と仮定し、検出力０．８以上、両側確率０．０５のαエラーを有する場合、両群の必要被験者数は３２人であった。ドロップアウト率を１０％と推定し、合計被験者数を７２と設定した。
<Statistical analysis>
In designing the sample size, past studies on the inhibitory effect of catechin beverages on acute upper respiratory tract inflammation (Reference 9: Nutrients (2019), 12 (1); 4), Relationship between NK activity and common cold frequency (Reference 10). : Environmental Health and Preventive Medicine (2000), 4 (4), p. 212-216), internal survey results of tea consumption and influenza incidence (data not disclosed) were referred to. The incidence of acute upper respiratory tract inflammation is assumed to be 27.0% in the test group and 64.8% in the comparative group, and both groups are required if they have an α error with a power of 0.8 or higher and a bilateral probability of 0.05. The number of subjects was 32. The dropout rate was estimated to be 10% and the total number of subjects was set to 72.
全被験者から、試験品を摂取しなかった被験者を除いた集団をＩｎｔｅｎｔｉｏｎ ｔｏ Ｔｒｅａｔ（ＩＴＴ）とした。ＩＴＴから中止・脱落した被験者を除いた集団をＦｕｌｌ Ａｎａｌｙｓｉｓ Ｓｅｔ（ＦＡＳ）とした。ＦＡＳから、以下の解析除外基準に該当する被験者を除いた集団をＰｅｒ Ｐｒｏｔｏｃｏｌ Ｓｅｔ（ＰＰＳ）とした。被験者の背景および有効性評価はＰＰＳ、安全性評価はＩＴＴで解析を行った。 The population excluding the subjects who did not ingest the test product from all the subjects was defined as Intention to Treat (ITT). The group excluding the subjects who were discontinued or dropped out of ITT was defined as Full Analysis Set (FAS). The population excluding the subjects who meet the following analysis exclusion criteria from the FAS was defined as the Per Protocol Set (PPS). The background and efficacy evaluation of the subjects were analyzed by PPS, and the safety evaluation was analyzed by ITT.
＜解析除外基準＞
（１）試験品の摂取率が８５％未満であった。
（２）日記とＷＵＲＳＳ－２１の入力率が８５％未満であった。
（３）被験者が、治験責任医師の指示に繰り返し違反した。
（４）被験者が、試験結果の信頼性を著しく損なう行動をとった。
（５）試験後に除外基準を満たすことが明らかになった。
（６）除外すべき他の明らかな理由があった。
<Analysis exclusion criteria>
(1) The intake rate of the test product was less than 85%.
(2) The input rate of the diary and WURSS-21 was less than 85%.
(3) The subject repeatedly violated the instructions of the investigator.
(4) The subject took an action that significantly impaired the reliability of the test results.
(5) After the test, it became clear that the exclusion criteria were met.
(6) There were other obvious reasons to exclude.
二値変数の比較にはフィッシャーの正確確率検定を使用した。連続データの平均値の違いは、スチューデントのｔ検定を行った。順序変数に基づく群間比較は、Ｗｉｌｃｏｘｏｎ順位和検定を行った。試験品とインフルエンザおよび急性上気道炎症発生率との関連性について、多重ロジスティック回帰分析を用いて、オッズ比（ＯＲ）および９５％信頼区間（ＣＩ）を算出した。共分散分析（ＡＮＣＯＶＡ）は、ＮＫ細胞活性と唾液ＳＩｇＡ濃度に関して被験者年齢による補正を行い、群間で比較するために行った。統計的有意性のしきい値は、Ｐ＜０．０５に設定した。統計処理にはＳＰＳＳ Ｓｔａｔｉｓｔｉｃｓ（ＩＢＭ社）、ＥＺＲ（Ｅａｓｙ Ｒ，自治医科大学、参考文献１１：Bone marrow transplantation，48(3)，p.452-458）バージョン１．４０を使用した。 Fisher's exact test was used to compare the binary variables. Student's t-test was performed for the difference in the mean value of continuous data. Wilcoxon rank sum test was performed for comparison between groups based on ordinal variables. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multiple logistic regression analysis for the association between the specimen and the incidence of influenza and acute upper respiratory tract inflammation. Analysis of covariance (ANCOVA) was performed to correct for NK cell activity and salivary SIgA concentration by subject age and to compare between groups. The statistical significance threshold was set to P <0.05. For statistical processing, SPSS Statistics (IBM), EZR (Easy R, Jichi Medical University, Reference 11: Bone marrow transplantation, 48 (3), p.452-458) version 1.40 was used.
《結果》
本試験で採取した連続データ中には定量上下限値を超えた値はなかったため、データの解析にはすべて実測値を用いた。
＜被験者背景の特徴＞
被験者の処置の流れを図１に示した。書面によるインフォームドコンセントを提供した申請者（ｎ＝１４５）は、自己管理調査に回答し、事前検査を受けた。７２名の被験者を選定し、各群３６人ずつ２群に割付けた。試験に参加した全被験者が試験を完遂したことから、ＩＴＴとＦＡＳは７２人であった。２人の被験者（各グループに１人）は試験品摂取開始時に急性上気道炎症を発症していたためＦＡＳから除外され、ＰＰＳは７０人（被験群３５人、比較群３５人）であった。事前の調査・検査の結果から、ＰＰＳの２群の背景には統計学的に有意な差は認められなかった（表２）。
"result"
Since none of the continuous data collected in this test exceeded the upper and lower limits of quantification, the measured values were used for all data analysis.
<Characteristics of subject background>
The flow of treatment of the subjects is shown in FIG. The applicant (n = 145) who provided informed consent in writing responded to the self-management survey and underwent pre-inspection. Seventy-two subjects were selected and assigned to two groups, 36 in each group. There were 72 ITTs and FASs, as all subjects who participated in the study completed the study. Two subjects (one in each group) were excluded from FAS because they developed acute upper respiratory tract inflammation at the start of test intake, and PPS was 70 (35 in the test group and 35 in the comparison group). From the results of the preliminary survey and examination, no statistically significant difference was observed in the background of the two groups of PPS (Table 2).
＜試験品摂取率＞
本試験では、被験者は１２週間、１日あたり任意のタイミングで３杯の試験品を摂取した。試験期間終了後、未開封の試験品の数が摂取の日誌記録と差異がないか確認した。ＰＰＳにおける試験品の摂取率は、摂取杯数では比較群で９９．６７±１．５７％、被験群で９９．９４±０．１４％であった。摂取日数では、比較群で９９．９７±０．２０％、被験群で１００．００±０．００％であった。群間で摂取率に統計学的な有意差はみられなかった。
<Test product intake rate>
In this study, subjects ingested 3 tablespoons of the test product at any time per day for 12 weeks. After the end of the test period, it was confirmed that the number of unopened test products was not different from the ingestion diary record. The intake rate of the test product in PPS was 99.67 ± 1.57% in the comparison group and 99.94 ± 0.14% in the test group in terms of the number of cups consumed. The number of days of intake was 99.97 ± 0.20% in the comparison group and 100.00 ± 0.00% in the test group. There was no statistically significant difference in intake rates between the groups.
＜急性上気道炎症およびインフルエンザ発現への影響＞
試験品摂取期間中の急性上気道炎症およびインフルエンザ（臨床診断あり）についての発生データを表３に示した。インフルエンザの臨床診断は、３７．８℃以上の発熱症状、または咳、喉の痛み、頭痛、筋肉痛のうちのいずれか２以上の症状が認められ、医師による診断結果に基づきインフルエンザの発症とした。急性上気道炎症については、試験期間中に発現した有害事象の中から急性上気道炎症に特徴的な症例を収集し、発生率、被験者あたりの発現回数、発現１回あたりの罹患日数を群間で比較した。ＰＰＳ解析では、急性上気道炎症の発現率は群間で有意差はなく、比較群で３７．１％（３５人中１３人）、被験群で１７．１％（３５人中６人）であり、被験者当たりの発現回数および１発現当たりの罹患日数においても有意差はなかったものの（オッズ比＝０．３５、９５％信頼区間＝０．１２－１．０７、Ｐ値＝０．１０６）、本発明の免疫増強剤の摂取によって大幅に減少していることが確認された。
<Effects on acute upper respiratory tract inflammation and influenza development>
Table 3 shows the outbreak data for acute upper respiratory tract inflammation and influenza (with clinical diagnosis) during the test product ingestion period. The clinical diagnosis of influenza was that fever of 37.8 ° C or higher, or any two or more of cough, sore throat, headache, and muscle pain were observed, and the onset of influenza was based on the diagnosis by a doctor. .. For acute upper respiratory tract inflammation, cases characteristic of acute upper respiratory tract inflammation were collected from the adverse events that occurred during the test period, and the incidence rate, number of occurrences per subject, and number of days of illness per occurrence were determined between the groups. Compared with. In PPS analysis, the incidence of acute upper airway inflammation was not significantly different between the groups, 37.1% (13/35) in the comparison group and 17.1% (6/35) in the test group. There was no significant difference in the number of occurrences per subject and the number of days affected per expression (odds ratio = 0.35, 95% confidence interval = 0.12-1.07, P value = 0.106). It was confirmed that the dose was significantly reduced by the intake of the immunopotentiator of the present invention.
試験品摂取開始後、インフルエンザワクチンを接種した被験者は７名（被験群５名、比較群２名）いた。ワクチン接種によってもたらされた獲得免疫および自然免疫強化の効果により、インフルエンザ症状が軽症化し、感染者は症状に気づかなかったか、一般的な風邪と判断して医師診察を受けなかった被験者がPPSに含まれる可能性が考えられた。そこで、層別解析としてワクチンを接種していない被験者のみを対象に急性上気道炎症への影響について検証を行った。インフルエンザワクチンの接種による影響を受けた７人の被験者を除外した層別解析では、急性上気道炎の発生率は、比較群（３９．４％、３３人中１３人）に対して、被験群（１０．０％、３０人中３人）で有意に低くなっていることが確認された（オッズ比＝０．１７，９５％信頼区間＝０．０４－０．６８，ｐ値＝０．００９）。さらに、被験者当たりの発現回数も比較群に比べ被験群の方が有意に少なかった（ｐ＝０．００８）。このことから、インフルエンザワクチンを非接種の場合において、特に本発明の免疫増強剤が有効となることが確認された。 After the start of ingestion of the test product, 7 subjects were vaccinated with influenza vaccine (5 in the test group and 2 in the comparison group). Due to the effects of adaptive immunity and enhanced natural immunity brought about by vaccination, influenza symptoms were alleviated, and subjects who did not notice the symptoms or did not see a doctor because they thought they had a common cold became PPS. It was possible that it would be included. Therefore, as a stratified analysis, we examined the effects on acute upper respiratory tract inflammation only in subjects who had not been vaccinated. In a stratified analysis excluding 7 subjects affected by influenza vaccination, the incidence of acute upper respiratory tract inflammation was higher in the test group than in the comparative group (39.4%, 13 of 33). It was confirmed that it was significantly lower in (10.0%, 3 out of 30) (odds ratio = 0.17, 95% confidence interval = 0.04-0.68, p-value = 0. 009). Furthermore, the number of occurrences per subject was also significantly lower in the test group than in the comparison group (p = 0.008). From this, it was confirmed that the immunopotentiator of the present invention is particularly effective when the influenza vaccine is not inoculated.
＜急性上気道炎症の発現に起因した症状の重症度および健康関連ＱＯＬ機能障害への影響＞
１２週間の試験品摂取期間中、急性上気道炎症状の重症度レベルとＱＯＬ妨害レベルのスコアはＷＵＲＳＳ－２１調査票を用いて毎日記録された。ワクチンを接種しなかった被験者６３人のうち４２人が、少なくとも１回は10項目の症状のうち1以上の症状について１点以上の重症度スコアを報告した。これら４２人の被験者（ｎ数：比較群＝２２、被験群＝２０）を対象とした層別解析により、試験品摂取期間中の症状重症度レベルおよびＱＯＬ妨害度レベルの合計スコアについて２群間で比較した結果を表４に示した。
<Severity of symptoms caused by the onset of acute upper respiratory tract inflammation and its effect on health-related quality of life dysfunction>
During the 12-week study period, the severity level of acute upper airway inflammation and the score of quality of life obstruction level were recorded daily using the WURSS-21 questionnaire. Forty-two of the 63 unvaccinated subjects reported a severity score of 1 or higher for at least one of the 10 symptoms at least once. By stratified analysis of these 42 subjects (n number: comparative group = 22, test group = 20), the total score of symptom severity level and QOL disturbance level during the test product intake period was between the two groups. The results of the comparison in Table 4 are shown in Table 4.
結果より、症状重症度レベルについて被験群（紅茶）は比較群（麦茶）に比べ、症状１０項目のうち５項目：「鼻水」（ｐ＝０．００７）、「鼻詰まり」（ｐ＝０．０４０）、「声がれ」（ｐ＝０．０３３）、「鼻詰まりによる頭部および顔面の圧迫感、重さ（表中では“頭部圧迫感“）」（ｐ＝０．０１１）および「疲労感」（ｐ＝０．００２）において有意にスコアが低く、「くしゃみ」症状（ｐ＝０．０６２）においては低くなる傾向が見られた。１０症状すべての重症度の合計スコアに関する中央値と２５～７５％値の範囲は、被験群で１３．５［３．５－４４．８］、比較群で５２［２３－１９６．３］、ウィルコクソン順位和検定に基づく群間比較のｐ値は０．０１５であった。これら結果から試験品摂取期間中において、被験群は比較群よりも急性上気道炎症の発現に起因する症状が軽かったことが確認された。 From the results, the test group (tea) had 5 out of 10 symptom items: "sneezing" (p = 0.007) and "stuffy nose" (p = 0.). 040), "sneezing" (p = 0.033), "tightening of the head and face due to stuffy nose, weight (" head tightness ")" (p = 0.011) and The score tended to be significantly lower in "fatigue" (p = 0.002) and lower in "sneezing" symptoms (p = 0.062). The median and 25-75% range for the total severity score of all 10 symptoms was 13.5 [3.5-44.8] in the test group and 52 [23-196.3] in the comparison group. The p-value for comparison between groups based on the Wilcoxon rank sum test was 0.015. From these results, it was confirmed that during the test product intake period, the test group had less symptoms due to the onset of acute upper respiratory tract inflammation than the comparative group.
また、ＱＯＬ妨害レベルについて被験群（紅茶）は比較群（麦茶）と比較して、９項目のうち４つのＱＯＬ項目「物事を明確に考えられる（表中では”嗜好“）」（ｐ＝０．０２５）、「熟睡する（表中では”睡眠“）」（ｐ＝０．０２４）、「楽に呼吸できる（表中では”呼吸“）」（ｐ＝０．０１１）および「家の中で仕事ができる（表中では”家事“）」（ｐ＝０．０３７）において有意に低いスコアであり、「他の人と交流ができる（表中では”外部交流“）」（ｐ＝０．０８９）および「自分の生活を楽しめる（表中では”生活の楽しみ“）」（ｐ＝０．０７８）の項目では低くなる傾向があった。９つの項目すべてのＱＯＬへの妨害レベルの合計スコアに関する中央値と２５～７５％値の範囲は、被験群で１．５［０．０－３．０］、比較群で５．５［０．３－６３．３］、ｐ値＝０．０５０で、有意に被験群でＱＯＬへの妨害が少なくなることが示された。これらの結果より、本発明の免疫増強剤を継続的に摂取することで、急性上気道炎症の発症リスクが低減するだけでなく、症状が軽減され、身体および精神的なダメージを効果的に低減できることが確認された。 In addition, regarding the QOL disturbance level, the test group (tea) was compared with the comparison group (wheat tea), and 4 of the 9 items were QOL items "things can be clearly considered (" preference "in the table)" (p = 0). .025), "Sleep soundly (" sleep "in the table)" (p = 0.024), "Breathe comfortably (" breathe "in the table)" (p = 0.011) and "in the house" The score is significantly lower in "I can work (" housework ") in the table" (p = 0.037), and "I can interact with other people (" external interaction ") in the table" (p = 0. 089) and "Enjoy your life (" Enjoy your life ")" (p = 0.078) tended to be lower. The median and 25-75% range for the total score of interference levels to QOL for all nine items was 1.5 [0.0-3.0] in the test group and 5.5 [0] in the comparison group. .3-63.3], with a p-value of 0.050, it was shown that there was significantly less interference with QOL in the test group. Based on these results, continuous ingestion of the immunopotentiator of the present invention not only reduces the risk of developing acute upper respiratory tract inflammation, but also reduces symptoms and effectively reduces physical and mental damage. It was confirmed that it could be done.
＜粘膜免疫系および全身免疫系指標値への影響＞
ＰＰＳ集団における、粘膜免疫系の指標として唾液分泌型ＩｇＡ抗体濃度、全身免疫系の指標として血清ＮＫ細胞活性値（Ｅ／Ｔ比１０：１）を測定した結果を表５に示す。被験群のみで、摂取終了時の唾液ＳＩｇＡ濃度の平均値は事前検査時よりも有意に増加したが（ｐ＝０．００７）群間での変化量の比較では有意差はなかった（ｐ＝０．２７５）。一方、ＮＫ細胞活性（Ｅ／Ｔ比１０：１）についても、被験群でのみ摂取終了時に有意な上昇が認められ（ｐ＝０．００２）、増加量は比較群よりも有意に多いことが示された（ｐ＝０．０３１）。また、エフェクター（Ｅ）とターゲット（Ｔ）の比率が異なるＮＫ細胞活性値（Ｅ／Ｔ比２０：１）においても、前後値の群内比較および変化量の群間比較の結果は前述と同様の結果になった。これらの結果から、本発明の免疫増強剤の摂取は唾液中のＳＩｇＡの増加とＮＫ細胞を活性化させることによって免疫を増強し、その結果として急性上気道炎症の発現を抑制する作用があることが確認された。
<Effects on mucosal immune system and systemic immune system index values>
Table 5 shows the results of measuring the salivary secretory IgA antibody concentration as an index of the mucosal immune system and the serum NK cell activity value (E / T ratio 10: 1) as an index of the systemic immune system in the PPS population. In the test group only, the average saliva SIgA concentration at the end of ingestion was significantly higher than that at the time of the pre-examination (p = 0.007), but there was no significant difference in the comparison of the amount of change between the groups (p = 0.007). 0.275). On the other hand, the NK cell activity (E / T ratio 10: 1) was also significantly increased at the end of ingestion only in the test group (p = 0.002), and the amount of increase was significantly larger than that in the comparative group. Shown (p = 0.031). Further, even in the NK cell activity value (E / T ratio 20: 1) in which the ratio of the effector (E) and the target (T) is different, the results of the intra-group comparison of the pre- and post-values and the inter-group comparison of the change amount are the same as described above. The result was. From these results, ingestion of the immunopotentiator of the present invention enhances immunity by increasing SIgA in saliva and activating NK cells, and as a result, has an effect of suppressing the onset of acute upper respiratory tract inflammation. Was confirmed.
免疫力は加齢により低下することが知られている（参考文献１２：Transplant International(2009), 22(11), p. 1041-1050）。そこで、共分散分析（ＡＮＣＯＶＡ）で年齢を共変量にしてＮＫ活性とＳＩｇＡ変化量を群間比較した（図２の（Ａ）：ＮＫ細胞活性、（Ｂ）：ＳＩｇＡ濃度）。その結果、ＮＫ活性では群間有意差（ｐ＝０．０３４）があり、両群の被験者年齢平均を４６．９才に調整した場合、ＮＫ活性の調整済み変化量（９５％信頼区間）は、比較群で＋０．３９（－１．０７～＋１．８５）％、被験群で＋２．６２（＋１．１６～＋４．０８）％であった。一方、ＳＩｇＡ濃度は群間有意差はなかった（ｐ＝０．３０３）が、比較群に比べて被験群の方が唾液ＳＩｇＡ濃度の変化量が大きくなる傾向が見られ、両群の被験者年齢平均を４６．９才に調整した場合、ＳＩｇＡ活性の調整済み変化量（９５％信頼区間）は、比較群で＋２０．００（－８．３１～＋４８．３２）μｇ／ｍＬ、被験群で＋４０．８１（＋１２．５０～＋６９．１３）μｇ／ｍＬであった。 It is known that immunity decreases with aging (Reference 12: Transplant International (2009), 22 (11), p. 1041-1050). Therefore, in analysis of covariance (ANCOVA), the NK activity and the SIgA change amount were compared between the groups by covariating the age ((A): NK cell activity, (B): SIgA concentration in FIG. 2). As a result, there was a significant difference (p = 0.034) between the groups in NK activity, and when the subject age average of both groups was adjusted to 46.9 years, the adjusted change in NK activity (95% confidence interval) was In the comparison group, it was +0.39 (-1.07 to +1.85)%, and in the test group, it was +2.62 (+1.16 to +4.08)%. On the other hand, there was no significant difference in SIgA concentration between the groups (p = 0.303), but the change in saliva SIgA concentration tended to be larger in the test group than in the comparison group, and the subject ages of both groups. When the average was adjusted to 46.9 years, the adjusted change in SIgA activity (95% confidence interval) was +20.00 (-8.31 to +48.32) μg / mL in the comparative group and +40 in the test group. It was .81 (+12.50 to +69.13) μg / mL.
そこで、事前検査時の唾液ＳＩｇＡ濃度の平均値（２００．４μｇ／ｍＬ）を境界としてＰＰＳを低ＳＩｇＡ被験者グループと高ＳＩｇＡ被験者グループに分けて解析を行った。表６に示した低ＳＩｇＡ（事前検査時の唾液ＳＩｇＡ濃度が２００．４μg／ｍＬ未満）被験者グループの結果より、被験群において摂取期間後の唾液ＳＩｇＡ濃度が摂取前よりも有意に高くなり（ｐ＝０．００３）、比較群よりも高値を示す傾向（ｐ＝０．０６７）が確認され、摂取前後の唾液ＳＩｇＡ濃度の変化量についても比較群に比べて被験群の方が大きくなる傾向（ｐ＝０．０５６）が見られた。また、ＮＫ細胞活性の有意な増加（ｐ＝０．００９）が認められるとともに、急性上気道炎症発症リスクの有意な低下（ｐ＝０．０４１）および発現頻度の有意な減少（ｐ＝０．０１８）が見られた。一方で、事前検査時の唾液ＳＩｇＡ濃度が２００．４μg／ｍＬ以上の被験者では被験品摂取による両免疫パラメータ変動影響は見られなかった。 Therefore, PPS was divided into a low SIgA subject group and a high SIgA subject group for analysis with the average value (200.4 μg / mL) of saliva SIgA concentration at the time of the pre-examination as a boundary. From the results of the low SIgA (saliva SIgA concentration at the time of pre-examination less than 200.4 μg / mL) subject group shown in Table 6, the saliva SIgA concentration after the ingestion period was significantly higher in the test group than before the ingestion (p). = 0.003), a tendency to show a higher value than the comparison group (p = 0.067) was confirmed, and the amount of change in saliva SIgA concentration before and after ingestion also tended to be larger in the test group than in the comparison group (p = 0.067). p = 0.056) was seen. In addition, a significant increase in NK cell activity (p = 0.009) was observed, a significant decrease in the risk of developing acute upper respiratory tract inflammation (p = 0.041), and a significant decrease in the frequency of occurrence (p = 0. 018) was seen. On the other hand, in the subjects whose saliva SIgA concentration at the time of the pre-examination was 200.4 μg / mL or more, the influence of the fluctuation of both immune parameters by the intake of the test product was not observed.
上記の結果から、本発明の免疫増強剤を継続的に摂取することにより、年齢の影響を受けずに血清ＮＫ細胞活性が有意に増加することが確認された。すなわち、老化による免疫機能低下の影響を受けず、本発明の免疫増強剤を継続的に摂取することにより、血清ＮＫ細胞活性は増加し、全身における自然免疫機能の強化につながったと考えられた。唾液ＳＩｇＡ濃度については、比較品摂取に比べて有意な増加は見られなかったが、摂取開始前に比べるとＳＩｇＡ濃度が有意に増加した。特に、唾液ＳＩｇＡ濃度が低い被験者においては、本発明の免疫増強剤を継続的に摂取することにより、唾液ＳＩｇＡ濃度の増加によって比較群よりも唾液中のＳＩｇＡ濃度が有意に高くなるだけでなく、ＮＫ細胞の活性化、急性上気道炎症の発症リスクおよび発現頻度が低減した。すなわち、唾液中のＳＩｇＡ濃度が低く粘膜免疫力が弱まった人は、本発明の免疫増強剤を継続的に摂取すると、粘膜免疫力が回復するだけでなく自然免疫力も高まり、感染を阻止して外来抗原を排除する生理学的防衛力（免疫力）が強化されることが期待できる。 From the above results, it was confirmed that continuous ingestion of the immunopotentiator of the present invention significantly increases serum NK cell activity without being affected by age. That is, it was considered that continuous ingestion of the immunopotentiator of the present invention without being affected by the decrease in immune function due to aging increased the serum NK cell activity and led to the enhancement of the innate immune function in the whole body. The saliva SIgA concentration was not significantly increased as compared with the intake of the comparative product, but the SIgA concentration was significantly increased as compared with that before the start of ingestion. In particular, in subjects with low saliva SIgA concentration, continuous ingestion of the immunopotentiator of the present invention not only significantly increases the SIgA concentration in saliva as compared with the comparative group due to the increase in saliva SIgA concentration, as well. Activation of NK cells, risk of developing acute upper airway inflammation and frequency of occurrence were reduced. That is, in a person whose SIgA concentration in saliva is low and the mucosal immunity is weakened, continuous ingestion of the immunity enhancer of the present invention not only restores the mucosal immunity but also enhances the natural immunity and prevents infection. It is expected that the physiological defense force (immunity) that eliminates foreign antigens will be strengthened.
＜安全性評価＞
有害事象は比較群および被験群の全ての症状について評価し、比較群で２６名に６１件、被験群で２３名に５３件の有害事象が認められたが、重度および重篤な有害事象は認められなかった。有害事象の発現率は比較群７２．２％（３６名中２６名）、被験群６３．９％（３６名中２３名）であり、統計学的有意差は認められなかった。試験品との因果関係が「おそらくあり」と判断された副作用として「嘔吐」が被験群で１例認められた。副作用の発現率は比較群０．０％（３６名中０名）、被験群２．８％（３６名中１名）で統計学的有意差は認められなかった（ｐ＝１．０００）。身体および生理学的計測、血液生化学および尿検査項目において、摂取開始後６週間、１２週間および摂取終了後４週間の値と事前検査時からの変化量は、いずれも群間で統計学的な有意差は認められなかった。
<Safety evaluation>
Adverse events were evaluated for all symptoms in the comparative and test groups, with 61 adverse events in 26 subjects and 53 adverse events in 23 subjects in the comparative group, with no serious or serious adverse events. I was not able to admit. The incidence of adverse events was 72.2% (26/36) in the comparison group and 63.9% (23/36) in the test group, with no statistically significant difference. One case of "vomiting" was observed in the test group as a side effect for which a causal relationship with the test product was judged to be "probably present". The incidence of side effects was 0.0% in the comparison group (0 out of 36) and 2.8% in the test group (1 out of 36), and no statistically significant difference was observed (p = 1.000). .. In physical and physiological measurements, blood biochemistry and urinalysis items, the values at 6 weeks, 12 weeks and 4 weeks after the start of ingestion and the changes from the pre-examination were all statistically statistical between the groups. No significant difference was observed.
Claims (7)
The immune enhancer according to claim 5 or 6, wherein the black tea exudate is orally ingested in an amount of 3 bags or more per day continuously for 12 weeks or more.
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