IL-18基因修饰的DC肿瘤融合瘤苗的抗肿瘤效应

Antitumor effect of interleukin 18 gene-modified DC-hepatoma fusion vaccine

目的 :观察腺病毒介导白细胞介素 1 8(Interleukin1 8,IL 1 8)修饰的小鼠树突状细胞 (Dendriticcells,DC)与Hep a1 6肝癌细胞融合后的瘤苗 (IL1 8 DC Hepa)体内诱导的抗肿瘤免疫应答以及对荷瘤小鼠的治疗效果 .方法 :应用T细胞与NK体内删除实验、4h51 Cr释放杀伤实验、酶联免疫吸附实验等方法 ,观察瘤苗对荷瘤小鼠免疫治疗作用及保护性免疫反应作用机制 .结果 :IL1 8 DC Hepa瘤苗组免疫治疗作用明显优于未转染IL 1 8的融合瘤苗组 (DC Hepa)和LacZ转染对照组 (LacZ DC Hepa) (P <0 .0 5 ) ,阻断CD4 + 、CD8+ T细胞都导致瘤苗免疫治疗作用明显降低 ,阻断NK细胞对抗肿瘤免疫应答具有一定影响 ,表明IL1 8 DC Hepa瘤苗的免疫治疗作用有赖于CD4 + 和CD8+ T细胞及NK细胞 .IL1 8 DC Hepa瘤苗体内诱导特异性CTL杀伤活性明显高于DC Hepa和LacZ DC Hepa组 (P <0 .0 0 1 ) ,诱导脾淋巴细胞产生IL 2和IFN γ的能力显著高于对照组DC Hepa和IL1 8 DC (P <0 .0 0 1 ) ,但各组瘤苗诱导脾淋巴细胞产生IL 4和IL 1 0能力无明显差异 (P >0 .0 5 ) ,表明IL 1 8主要是通过诱导IL 2和IFN γ等Th1型细胞因子来增强DC融合瘤苗的抗肿瘤效应 .结论 :IL1 8 DC Hepa瘤苗进行体内免疫保护和治疗 ,能诱导出显著的抗肿瘤免疫反应 。

AIM: To investigate the induction of antitumor immune response and therapeutic effect of the IL18 DC Hepa fusion vaccines by adenovirus mediated IL 18 gene modified DC fused with hepal 6 from hepatoma. METHODS: Protective and therapeutic effects of the fusion vaccine were detected by in vivo depletion of T cells and NK cells assay, 4 h 51 Cr releasing assay, ELISA. RESULTS: IL18 DC Hepa vaccine was found to be more potent in antitumor immune response than DC Hepa vaccine and LacZ gene transfected LacZ DC Hepa vaccine ( P <0.05). Depletion of CD4 + and CD8 +T cells significantly eliminated the protective effect of the IL18 DC Hepa vaccine, and depletion of NK cells had less significant influence on protective effects than that of CD4 + and CD8 +T cells. These data indicate that CD4 +、CD8 +T cells and NK cells are required for effective antitumor immunity induced by IL18 DC Hepa vaccine. CTL activity was significantly higher in lymphocytes from IL18 DC Hepa immunized mice than in those from DC Hepa and LacZ DC Hepa immunized mice ( P <0.001). Immunization with IL18 DC Hepa vaccine led to the significantly higher amount production of IL 2 and IFN γ than immunization with DC Hepa and IL18 DC ( P <0.001), but there were no significant difference in the production of the amount of IL 4 and IL 10 in all the groups ( P >0.05). These data indicate that Il 18 enhances antitumor immune response by promoting generation of Th1 cells. CONCLUSION: IL18 DC Hepa fusion vaccines could elicit potent antitumor responses, which will provide a new approach to the gene modified DC mediated therapeutic antitumor immunity.