| Project/Area Number |
12470245
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
IMANISHI Jiro Kyoto Prefectural University of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (40112510)
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| Co-Investigator(Kenkyū-buntansha) |
MAZDA Osam Kyoto Prefectural University of Medicine, Faculty of Medicine, Associate Professor, 医学部, 助教授 (00271164)
UEDA Yuji Kyoto Prefectural University of Medicine, Faculty of Medicine, Assistant Professor, 医学部, 助手 (60254356)
YAMAGISHI Hisaichi Kyoto Prefectural University of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (40128723)
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| Project Period (FY) |
2000 – 2001
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| Keywords | gene therapy / IL-1 8 / Cancer / tumor immunity / nonviral vectors / cationic lipid / electroporation / tumor vaccine |
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| Research Abstract |
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
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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
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