| Project/Area Number |
13557097
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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 | 展開研究 |
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| Research Field |
General surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TAKEDA Yasutaka The University of Tokyo, Institute of Medical Science, Clinical Associate, 医科学研究所, 助手 (40163422)
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| Co-Investigator(Kenkyū-buntansha) |
TSUBURA Airo The Kansai Medical College, Department of Pathology, Professor, 医学部, 教授 (90098137)
SHIMIZU Motomu The Tokyo Metropolitan Organization for Medical Research, Medical R&D center, Senior Researcher, 東京都臨床医学総合研究所, 主任研究員 (10124463)
YOSHIMOTO Takayuki The Tokyo Medical College, Intractable Disease Research Center, Associate Professor, 難病治療研究センター, 助教授 (80202406)
YANAGIE Hironobu University of Tokyo, Research Center for Advanced Science and Technology, Associate Professor, 先端科学技術研究センター, 特任助教授 (30212278)
ERIGUCHI Masazumi The University of Tokyo, Research Center for Advanced Science and Technology, Professor, 先端科学技術研究センター, 特任教授 (10114406)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2003: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2002: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2001: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Keywords | FasL(CD95L)-transfected tumor cell / Cancer Gene therapy / Nonviral vector / Gene delivery / Liposome / Anti-tumor effect / Apoptosis / Chemokine / Fasリガンド / マクロファージ / 好中球 / 抗腫瘍効果 |
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| Research Abstract |
CD95 ligand (FasL)-expressing tumors cause immunopotentiation following vigorous neutrophil infiltration. Thus, the induction of neutrophil Infiltration by FasL appears to play an important role in tumor rejection. 1) The mechanism by which FasL-expressing tumors cause neutrophil infiltration has not been well understood. Here, we Investigated the role of chemokines in FasL-induced antitumor activity. CXC chemokine receptor 2 (CXCR2) knockout (KO) mice are a powerful tool for studying CXC chemokine-mediate neutrophil infiltration. Thus, we examined the mechanism for the neutrophil recruitment Induced by FasLcDNA-transfected MethA (MethA+FasL) fibrosarcoma using CXCR2 KO mice. MethA+FasL cells were completely rejected in wild-type (WT) and KO mice. MethA+FasL cells Injected i.p. induced the recruitment of both neutrophils and macrophages in peritoneal cavity (PC) of WT but only macrophages in PC of KO mice, although CXC and CC chemokines were released In PC in both mice. Macrophages Inc
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ubated with MethA+FasL cells released CXC and CC chemokines. F4/80-positive macrophages decreased after injection of MethA+FasL cells. Macrophages derived from WI and KO but not neutrophils from WT mice induced the recruitment of neutrophils when adoptively i.p. transferred with MethA+FasL cells into FasL/Fas-deficient mice. The different recruitment of inflammatory cells between WT and KO mice was attributed to bone marrow (BM) cells by BM transfer experiment. These results demonstrated that CXC chemokines are essential for neutrophil recruitment and that macrophages but not neutrophils play a critical role in FasL-induced infiltration of Inflammatory cells and that chemokines played important roles In eradication of FasL-expressing tumor cells and induction of antitumor immunity. 2) Mouse mammary tumor, BJMC3879, has highly metastatic potential. FasLcDNA-transfected BJMC3879 (BJMC+FasL) was established for clinical application of breast cancer. Although It induced neutrophil recruitment, It was not rejected In WT mice. The reason might be that BJMC+FasL was little expressed FasL-protein on cell surface. It could be indicated that the capability of FasL-protein expression depends on a kind of tumor cell. 3) On the other hand, we were developing non-viral vectors for clinical application. We are investigating the effects of Quarternary complex (Qplex) (cDNA+cationlc liposome+protamine+transferin) or polyethilenimine on transfecting rate of a few cell lines. Several problems for clinical application become clear. Less
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