サイトカインによる担癌宿主T細胞の応答制御

• 研究課題/領域番号: 06282234
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 大阪大学
• 研究代表者: 濱岡 利之 (浜岡 利之) 大阪大学, 医学系研究科, 教授 (60028529)
• 研究分担者: 小野 史郎 大阪大学, 医学系研究科, 助教授 (80127208) ; 緒方 正人 大阪大学, 医学部, 助手 (60224094)
• 研究期間 (年度): 1994 – 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 120,000千円 (直接経費: 120,000千円); 1999年度: 30,000千円 (直接経費: 30,000千円); 1998年度: 30,000千円 (直接経費: 30,000千円); 1997年度: 15,000千円 (直接経費: 15,000千円); 1996年度: 15,000千円 (直接経費: 15,000千円); 1995年度: 15,000千円 (直接経費: 15,000千円); 1994年度: 15,000千円 (直接経費: 15,000千円)
• キーワード: インターロイキン12 / 担癌状態 / T細胞浸潤 / 腫瘍拒絶抗原 / 免疫抑制 / 抗腫瘍機構 / 腫瘍特異免疫 / T細胞-血管内皮細胞相互作用 / 担癌 / IL-12 / IFN-γ / 浸潤 / 血管内皮細胞 / 接着分子 / CD40L / 抗腫瘍免疫 / CTLA-4 / 腫瘍免疫 / iNOS / IDO / リンパ球浸潤 / 担癌宿主 / サイトカインネットワーク / 免疫増強 / T細胞レセプター / TGF-β / IL-6

研究概要

担癌状態では癌拒絶抗原提示能を持ったAPC機能は正常であり、抗腫瘍T細胞は担癌早期では一旦は活性化される。しかし癌の進行に伴い応答性が抑制されていく。ここで強調すべきは、一旦誘導された抗腫瘍T細胞は担癌状態の進行により消去されずに、一時的に機能異常が惹起されている点である。ちなみにBALB/Cマウス由来CSA-1M線維肉腫細胞や(B6xC3H)F1マウス由来OV-HM卵巣癌細胞担癌マウスにIL-12を投与すると、腫瘍の完全退縮及び著明な抗腫瘍転移効果を誘導できる。しかも、IL-12投与は抑制された抗腫瘍T細胞のIFN-γ産生能を著明に回復/増強する。またIL-12投与により腫瘍が退縮したマウスでは腫瘍特異免疫が獲得されている。IL-12の抗腫瘍効果は全ての腫瘍系で有効とは限らず、効果をほとんど認めない非奏効性腫瘍系が存在する事がわかった。そして腫瘍周辺部ストローマ形成の有無が、腫瘍局所への抗腫瘍性T細胞浸潤を、更にはIL-12治療の効果を左右する重要な因子である事を報告した。今回、担癌T細胞応答性低下の免疫分子環境を解析した結果、担癌宿主ではとりわけ担癌後期で脾臓中にMac-1陽性のGr-1陽性細胞の著しい増加が認められ、その結果NO産生が増加し、IFN-γ産生に代表されるT細胞応答性が抑制される。しかしT細胞がこのような環境から解放されると、速やかにそれ自身の持つ応答性を回復しうる。またT細胞自身のIL-12応答性は、担癌ステージに関らず差がみられない事が明らかになった。またIL-12によるT細胞腫瘍組織内浸潤の誘導に重要な役割を果たす腫瘍周囲ストローマ形成にはIL-12治療前から腫瘍塊に少数ながらも浸潤しているCD4^+/CD8^+T細胞及びそれらが産生する少量のIFN-γが必要であることより、腫瘍周辺部ストローマの形成は宿主免疫系と腫瘍の相互作用に基づく事が示唆された。

研究成果

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