自己・非自己識別分子MHCの起源と進化

• 研究課題/領域番号: 05304003
• 研究種目: 総合研究(A)
• 配分区分: 補助金
• 研究分野: 遺伝
• 研究機関: 総合研究大学院大学
• 研究代表者: 高畑 尚之 総合研究大学院大学, 教育研究交流センター, 教授 (30124217)
• 研究分担者: 堀 寛 名古屋大学, 理学部, 教授 (60116663) ; 池村 淑道 国立遺伝学研究所, 集団遺伝研究系, 教授 (50025475) ; 笠原 正典 北海道大学, 医学部, 助教授 (30241318) ; 小幡 裕一 愛知県がんセンター, 免疫学部, 室長 (30177290) ; 笹月 健彦 九州大学, 生体防御医学研究所, 教授 (50014121)
• 研究期間 (年度): 1993 – 1994
• 研究課題ステータス: 完了 (1994年度)
• 配分額: 20,400千円 (直接経費: 20,400千円); 1994年度: 9,500千円 (直接経費: 9,500千円); 1993年度: 10,900千円 (直接経費: 10,900千円)
• キーワード: クローニング / 下等脊椎動物MHC / 非古典的MHC / HLA / 自己免疫 / MHC拘束 / 起源と進化 / T細胞レパートリー

研究概要

自己・非自己識別分子MHCの起源は、脊椎動物の出現時期とほぼ同一であることが明らかになった。橋本や笠原は、世界に先駆けて軟骨魚類のMHCの単離に成功し、その多様性のあり方が基本的には哺乳類のものと同じであることを示した。堀は魚類におけるMHCの遺伝子構成に注目し、3種のクラスII遺伝子群の存在を確認した。しかし、より下等な無鰐類からMHC遺伝子を単離する試みはすべて失敗に終わっていて、その他の知見と合わせMHC分子の出現が無鰐類の出現以降であったことが示唆された。以上は脊椎動物免疫系の起源が5億程前のカンブリア紀であり、このときMHCの他に免疫グロブリンやT細胞受容体分子なども同時に進化したことを示している。自己・非自己識別に重要な役割を担っている分子は古典的MHCであるが、機能が不明確な非古典的MHCも多数存在する。小幡、森脇と高畑はマウスの非古典的MHCであるTLに注目し、腸で強く発現することの生物的意義が特種な寄生体への対応であるという仮説をたてた。これを検証するためにTL特異的に結合するペプチドの単離を急いでいる。これは中枢免疫と局所免疫の関係など新しい問題を含んでいる。ヒトMHC(HLA)領域の遺伝的多様性と様々な疾患を明らかにするため、猪子、池村と笹月は4Mb領域の遺伝解析を進め、遺伝子密度、GC量、組換えホットスポット、DNAの複製点などの同定を行った。このことから疾患がおこる分子機構や脊椎動物のゲノム進化の道筋を解明する手がかりを得た。以上の成果は、世界的にみても第一級のものである。また班員間の研究協力も十分に進み添付リストにあるように班員の共著論文が多数発表された。

研究成果

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