Gene Therapy and Cell Therapy of Cancer by Means of the Interleukin-18 Gene Transfer

IL-18最初被认为是干扰素-γ的诱导因子。IL-18可增强CTL和NK细胞的细胞毒活性，并与IL-12协同产生干扰素-γ。IL-12在诱导细胞免疫反应中起关键作用。它能增强细胞毒性T淋巴细胞(CTL)和自然杀伤细胞(NK)的增殖和杀伤活性。IL-12还促进辅助性T细胞1型应答，并诱导干扰素-γ的产生。因此，转导IL-12和IL-18基因可以增强特异性和非特异性的抗肿瘤免疫应答。EBV载体与非病毒载体联合导入哺乳动物细胞后，效果明显优于传统的载体载体。这些系统对于癌症基因治疗的基因治疗是非常有用的。我们用小鼠IL-18基因表达盒构建了基于EBV的表达载体。…体内转导IL-18基因到小鼠体内预建瘤的研究更多的是电穿孔，或通过阳离子聚合物(肿瘤疫苗)体外进入培养的肿瘤细胞系。体内和体外系统均实现了细胞因子基因的高效表达，而IL-18在体内系统中表现出相当好的抗治疗作用。体内IL-18基因转移，特别是IL-12基因共转染，成功地诱导了特异性和非特异性抗肿瘤免疫应答。体外实验结果有力地表明，EBV/Lipoplex在操纵有效的肿瘤细胞疫苗方面是非常有用的，该疫苗能强烈地产生IL-12和IL-18，从而激发针对肿瘤的强大的Th1免疫反应。这些高效的基因转移系统可能使设计无药物选择的自体肿瘤疫苗成为可能。结论：IL-18基因转移可能为治疗恶性肿瘤，特别是转移性肿瘤提供强有力的策略。较少

IL-18 is originally identified as the IFN-g inducing factor. IL-18 augments cytotoxic activities of CTL and NK cells, and synergizes with effectiveness of IL-12 in the IFN-g production. IL-12 plays critical roles in the induction of the cell-mediated immune responses. It augments proliferation and killing activity of cytotoxic T lymphocyte (CTL) as well as natural killer (NK) cells. IL-12 also facilitates T helper type 1 (Th1) response and induces interferon (IFN)-γproduction. Therefore, transduction of IL-12 and IL-18 genes may enhance both specific and nonspecific anti-tumor immune responses.The EBV plasmids give considerably better results than conventional plasmid vectors when transfected into mammalian cells in combination with any nonviral vehicles. These systems are quite useful for gene therapy of cancer gene therapy. We constructed EBV-based plasmid vectors with murine IL-18 gene expression cassettes. The IL-18 gene was transduced in vivo into preestablished tumor in mice thro … More ugh electroporation, or ex vivo into cultured tumor cell lines via cationic polymer (tumor vaccine). Both in vivo and ex vivo systems achieved quite efficient expression of the cytokine gene, and IL-18 showed quite good anti-therapetic effects especially in vivo systems. Cotransfection with IL-12 gene showed further higher therapeutic outcome, showing that the EBV system enable efficient immuno-gene therapy.The present findings also suggest that the IL-18 gene transfer in vivo, especially when IL12 gene is cotransfected, successfully leads to both specific and non-specific anti-tumoral immune responses. The results from ex vivo experiments strongly suggest that the EBV/lipoplex is quite useful in manipulating an effective tumor cell vaccine that strongly produce IL-12 and IL-18 eliciting powerful Th1 immune responses against tumors. These highly efficient gene transfer system may make it possible to engineer autologous tumor vaccine without drug selection.In conclusions, the IL-18 gene transfer may provide powerful strategies against malignancies, especially metastatic tumors. Less