がん免疫寛容のメカニズムとその制御

• 研究課題/領域番号: 06282103
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 千葉大学
• 研究代表者: 谷口 克 千葉大学, 大学院・医学研究所, 教授 (80110310)
• 研究分担者: 江浦 正郎 熊本大学, 医学部附属病院, 講師 (60193984) ; 西村 孝司 東海大学, 医学部, 助教授 (30143001) ; 藤原 大美 大阪大学, 医学部, 助教授 (70116094) ; 奥村 康 順天堂大学, 医学部, 教授 (50009700) ; 西村 泰治 熊本大学, 医学部, 教授 (10156119) ; 石川 哮 熊本大学, 医学部, 教授 (00009143) ; 高橋 利忠 愛知県がんセンター研究所, 免疫学部, 副所長 (00124529) ; 渡辺 武 九州大学, 生体防御医学研究所, 教授 (40028684) ; 中島 泉 名古屋大学, 医学部, 教授 (40022826) ; 佐藤 昇志 札幌医科大学, 医学部, 教授 (50158937) ; 古川 鋼一 長崎大学, 医学部, 助教授 (80211530) ; 栗林 景容 三重大学, 医学部, 教授 (10064578)
• 研究期間 (年度): 1998
• 研究課題ステータス: 完了 (1998年度)
• 配分額: 134,000千円 (直接経費: 134,000千円); 1998年度: 29,000千円 (直接経費: 29,000千円); 1997年度: 29,000千円 (直接経費: 29,000千円); 1996年度: 30,000千円 (直接経費: 30,000千円); 1995年度: 23,000千円 (直接経費: 23,000千円); 1994年度: 23,000千円 (直接経費: 23,000千円)
• キーワード: がん免疫 / ドレランス / サイトカイン / NKT細胞 / IL-12 / 養子免疫療法 / トレランス / 免疫寛容 / MHCペプチド / T細胞エピトープ / 補助シグナル / がん抗原 / キラーT細胞 / TIL / T細胞レパトア / クラスIMHC / ペプチドモチーフ

研究概要

がんに対する末梢性免疫寛容成立の機序とその制御メカニズムを検討した。そのために(1)抗原認識分子を介する末梢性免疫寛容成立機序とその人為的阻害の基礎研究、(2)免疫制御細胞による末梢性免疫寛容性の機序とその制御に関する研究、 (3)特異的CTLを用いた養子免疫による末梢性免疫寛容からの回復を目指したがん治療法の研究、の3つの観点から研究を行い、下記の諸点を明らかにした。
1) TEL/AMLl融合ペプチドの1アミノ酸置換アナログペプチドは、CD4T細胞の活性化/IFNγ産生を約10倍に増強した。
2) CD40L遺伝子導入により、IL-12によるNK/NKT細胞の活性化、B7発現誘導による特異的T細胞活性化を起こし、特異的抗腫瘍免疫を効果的に誘導できた。
3) IL-12治療による腫瘍退縮には、peritumoralストローマ血管の接着分子発現増強とそれによるT細胞が腫瘍塊に浸潤が必要であった。
4) NKTリガンドα-GalCerは、CD40/CD40L依存的にDCのIL-12産生とNKTのIL-12受容体を発現増強させ免疫増強効果を出す。さらに、IL-12とα-GalCerとの併用は相乗的に働き、IFNγ産生/NK活性化が著しく増強され、癌治療への有用性が示された。
5) ヒトNKT細胞のリガンドもα-GalCerである事を証明し、活性化ヒトNKT細胞は広範にヒト腫瘍を障害し臨床応用に道を開いた。
6) MAGE-3抗原由来のHLA-A24分子結合性癌拒絶抗原を新しく同定した。しかしながら、頭頸部扁平上皮癌患者においてペプチド特異的CTLの誘導は困難であった。
7) 特異的CD4T細胞とCD8CTLの協同作用で最も強い腫瘍の拒絶がみられた。それは担癌末期状態で低下するCD8T細胞のCD3zeta分子の表現をCD4T細胞が回復し、CTLを活性化する事を見い出した。

研究成果

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