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

IL-18最初被鉴定为IFN-g诱导因子。IL-18增强CTL和NK细胞的细胞毒活性，并在IFN-γ产生中与IL-12的有效性协同。IL-12在诱导细胞介导的免疫应答中起关键作用。它增强细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞的增殖和杀伤活性。IL-12还促进1型辅助性T细胞（Th1）应答并诱导干扰素（IFN）-γ产生。因此，IL-12和IL-18基因的转导可以增强特异性和非特异性抗肿瘤免疫应答。这些系统对于癌症基因治疗是非常有用的。我们用鼠IL-18基因表达盒构建了基于EBV的质粒载体。将IL-18基因导入小鼠体内预先建立的肿瘤， ...更多信息 通过电穿孔，或通过阳离子聚合物离体进入培养的肿瘤细胞系（肿瘤疫苗）。体内和体外系统均实现了细胞因子基因的相当有效的表达，并且IL-18尤其在体内系统中显示出相当好的抗治疗作用。与IL-12基因共转染的治疗效果更好，表明EBV系统能够有效地进行免疫基因治疗，同时IL-18基因的体内转染，特别是IL-12基因的共转染，成功地诱导了特异性和非特异性抗肿瘤免疫应答。离体实验的结果强烈表明，EBV/lipoplex在操纵有效的肿瘤细胞疫苗中是非常有用的，所述肿瘤细胞疫苗强烈产生IL-12和IL-18，引发针对肿瘤的强大的Th1免疫应答。这些高效的基因转移系统的建立，为不经药物筛选的自体肿瘤疫苗的研制提供了可能，IL-18基因转移为恶性肿瘤尤其是转移性肿瘤的治疗提供了新的思路。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