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

通过IL-18基因转移进行癌症的基因治疗和细胞治疗

• 批准号: 12470245
• 负责人: IMANISHI Jiro
• 金额: $ 3.14万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470245/
• 关键词: gene therapy; IL-1 8; Cancer; tumor immunity; nonviral vectors; cationic lipid; electroporation; tumor vaccine; カチオニックポリマー

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

IL-18最初被确定为IFN-g诱导因子。IL-18增强了CTL和NK细胞的细胞毒活性，并与IL-12协同作用于IFN-g的产生。IL-12在诱导细胞介导的免疫应答中起关键作用。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T辅助型1 （Th1）反应并诱导干扰素(IFN)-γ的产生。因此，IL-12和IL-18基因的转导可能增强特异性和非特异性抗肿瘤免疫反应。当与任何非病毒载体联合转染到哺乳动物细胞中时，EBV质粒比常规质粒载体的效果要好得多。这些系统对癌症基因治疗非常有用。我们构建了以ebv为载体的鼠IL-18基因表达载体质粒。IL-18基因通过电穿孔在体内转入小鼠预建立的肿瘤，或通过阳离子聚合物（肿瘤疫苗）在体外转入培养的肿瘤细胞系。在体内和离体系统中均能高效表达细胞因子基因，IL-18在体内系统中表现出较好的抗治疗作用。与IL-12基因共转染显示出更高的治疗效果，表明EBV系统能够有效地进行免疫基因治疗。目前的研究结果还表明，IL-18基因在体内的转移，特别是当il - 12基因被共转染时，成功地导致特异性和非特异性抗肿瘤免疫反应。离体实验的结果有力地表明，EBV/脂质体在操纵一种有效的肿瘤细胞疫苗方面非常有用，这种疫苗能强烈地产生IL-12和IL-18，从而引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使无需药物选择的自体肿瘤疫苗的研制成为可能。总之，IL-18基因转移可能提供了对抗恶性肿瘤，特别是转移性肿瘤的有效策略。少

项目成果

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