感染症と免疫病の分子生物学と医学

1998 Fiscal Year Annual Research Report

• Project/Area Number: 09CE2007
• Research Institution: Osaka University
• Principal Investigator: 岸本 忠三 大阪大学, 医学部, 総長 (10093402)
• Co-Investigator(Kenkyū-buntansha): 菊谷 仁 大阪大学, 微生物病研究所, 教授 (80161412) ; 清野 宏 大阪大学, 微生物病研究所, 教授 (10271032) ; 木下 タロウ 大阪大学, 微生物病研究所, 教授 (10153165) ; 山西 弘一 大阪大学, 医学部, 教授 (10029811)
• Keywords: 感染症 / 免疫病 / サイトカイン / インターロイキン6 / ヒトヘルペスウイルス / GPIアンカー / CD40 / 粘膜免疫

Research Abstract

(岸本グループ)
1) サイトカインのnegative feedback因子であるSSI-1・の生体内での機能を、そのノックアウトマウスの作製により解析した。作製されたマウスは発育不良、早期死亡を呈し、また免疫系細胞のアポトーシスが亢進していた。その機序としてSSI-1が腫瘍壊死因子(TNF)のシグナル伝達を阻害していることを示唆した。
2) プレB細胞増殖因子PBSFの受容体であり同時にHIVの第二受容体でもあるCXCR4欠損マウスを作製した。作製されたマウスは血球系細胞の著減、血管形成の不全など、PBSF欠損マウスと類似の形質を呈し、PBSFとCXCR4の一対一のリガンド・受容体関係が明らかになった。
3) 無ガンマグロプリン血症の責任遺伝子であるBtkの、Bリンパ球内のカルシウム関連シグナル伝達における意義を明らかにし、またBtkの活性抑制因子を同定した。
(山西グループ)
1) HHV-6Bの潜伏感染時に発現するmRNAを5種類見出した。次に、HHV-6Bと近縁であるヒトヘルペスウイルス7の潜伏感染遺伝子を一部同定した後、HHV-6Bのものと比較し、両者に保存されている蛋白を見出した。さらに、この保存されている蛋白は、Yeast Two-hybrid systemにより、血球系細胞のシグナル伝達に重要な働きをもつ、CyclophilinBリガンド(CAML)と結合する事が判明した。
2) HHV-6Bにコードされるケモカイン遺伝子U83どケモカイン受容体遺伝子U12を同定し、両分子とも機能性であることを示した。
3) ヒ卜へルペスウイルス8にコードされるウイルス性のIL-6がヒトのIL-6の産生を誘導する事を示し、キャッスルマン氏病の病因を示唆した。
(木下グループ)
1) GPIアンカー欠損細胞を血液系だけに持つ発作性夜間血色素尿症の新しいモデルマウスを作成した。このマウスの解析から、異常造血幹細胞の拡大には第2の要因が必須であること、GPIアンカー型タンパク質がT細胞の分化初期における増殖の負の制御に関わっていること、またB細胞の血液からリンバ組織への移行に重要であることがわかった。
2) 新規のGPI欠損変異細胞を発見し、第1のマンノースの付加に異常があることを示した。さらにその異常を相補する新規の生合成遺伝子PIG-Mをクローニングした。
3) トリパノソーマ、ブルセイのPIG-Bをノックアウトし、GPIアンカーが血流型の生存に必須であること、昆虫型の増殖にも非常に重要であることを示した。さらに、化学療法の有力な標的と考えられるGPIトランスアミダーゼのコンポーネントであるGPI8をクローニングした。
(清野グループ)
1) 炎症性腸疾患(IBD)発症の引き金となりうる禁止T細胞クローンのTCRの解析を進め、β鎖のホモダイマー(_<ββ>T細胞)というまったく新規のTCRを発現していることを見い出した。
2) 粘膜ワクチン開発を視野にいれて、呼吸器系粘膜免疫機構の解析を進めNALTにおけるTh1型、Th2型誘導機構を明らかにした。病原微生物由来抗原(例、PspA,p55gag)を粘膜アジュバントを併用して経鼻免疫することによりNALTを介して粘膜系と全身系に抗原特異的免疫応答が誘導されることを示した。
3) ヒトへの応用をふまえて遺伝子操作により開発された無毒化CTの粘膜アジュバント作用機序についての解析を進め、CTがスーパー抗原により誘導されるCD4^+T細胞のアナジー化を回避しヘルパー機能を維持させる働きがあることが分かった。
(菊谷グループ)
1) CD40からは少なくとも二種のシグナルが伝達され、B細胞の活性化、分化とクラススイッチには膜近位部からのシグナル、胚中心形成には膜遠位部からのシグナルが必要であることを示した。
2) EBウイルスの形質転換因子LMP1がCD40シグナルと同様にクラススイッチを含むリンパ濾胞外B細胞活性化と分化を誘導するが、胚中心B細胞分化を抑制することを示した。
3) CD100がCD40シグナルの標的遺伝子産物であり、クラススイッチを増強することを示した。
4) CD40欠損マウスではT細胞の自己反応性が上昇すること、更にこの自己反応性の上昇は、CD40-CD40L相互作用非存在下では抑制性T細胞が出現しないためであることを明らかにした。
5) NOD由来自己膵島反応性T細胞が認識するペプチドのモチーフを決定した。

Research Products

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