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IL-12との併用におけるIL-18の抗腫瘍効果の増強と作用機序の検討：大崎　匡^1,2、橋元　亘²、Andrea Gambotto³、岡村　春樹⁴、Paul D. Robbins³, 栗本雅司⁵, Michael T. Lotze^2,3, 田原　秀晃^2,3 （¹阪大・医・３内、²ピッツバーグ大・医・外、³ピッツバーグ大・医・分子遺伝、生化 ⁴兵庫医大、ハイテク、生体防御 、⁵林原生化研、藤崎研）

Analyses on mechanisms of antitumor effects of IL-18 and their enhancement in combination with IL-12: Tadashi OSAKI^1,2, Wataru HASHIMOTO², Andrea GAMBOTTO³, Haruki OKAMURA⁴, Paul D. ROBBINS³, Masashi KURIMOTO⁵, Michael T. LOTZE^2,3, and Hideaki TAHARA^2,3 (¹Dept. of Med. III, Osaka Univ. Med. Sch., ²Dept. of Surg., ³Dept. of Mol. Genet. & Biochem., Univ. of Pittsburgh, ⁴Div. of Host Defenses, Inst. for Adv. Med. Sci., Hyogo College of Med., ⁵Fujisaki Inst., Hayashibara Biochem. Lab.)

We have reported that IL-18 shows significant anti-tumor effects, but with some limitations. To enhance anti-tumor effects of IL-18, we administered recombinant (r) IL-12 combined with systemic administration of rIL-18 or local IL-18 expression using peritumoral (p.t.) injections of an IL-18 adenoviral vector (Ad.PTH.IL-18). Systemic administration of rIL-18 combined with rIL-12 significantly suppressed growth of established tumor in vivo, however, caused lethal side effects mainly due to highly elevated IFN-γlevels in the serum. The p.t. injections of Ad.PTH.IL-18 completely eradicated tumors in all animals when combined with systemic administration of rIL-12 without apparent side effects or elevation of serum IFN-γlevels. IL-18 showed its anti-tumor effects independent of endogeneous IL-12 or induced IFN-γ. Depletion of asialo-GM1⁺ cells completely and depletion of CD4⁺ or CD8⁺ cells partially abrogated the anti-tumor effects of IL-18. Immunohistochemical analysis revealed that administration of IL-18 was associated with the reduced number of CD8⁺ cells within tumor. In conclusion, IL-18 gene therapy combined with systemic rIL-12 administration has better anti-tumor effects with less toxicity when compared with systemic rIL-18 administration.