| Project/Area Number |
10470090
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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 |
Immunology
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| Research Institution | Kanazawa University |
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Principal Investigator |
SUDA Takashi Kanazawa Univ., Cancer Res. Inst., Prof., がん研究所, 教授 (70250090)
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| Co-Investigator(Kenkyū-buntansha) |
IMAMURA Ryu Kanazawa Univ., Cancer Res. Inst., Assist. Prof., がん研究所, 助手 (10311680)
NAGATA Shigekazu Osaka Univ. Med. Schl., Prof., 医学部, 教授 (70114428)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥10,700,000 (Direct Cost: ¥10,700,000)
Fiscal Year 1999: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1998: ¥5,900,000 (Direct Cost: ¥5,900,000)
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| Keywords | Fas ligand / apoptosis / T lymphocytes / GVHD / anti-Fas ligand antibody / inflammation / caspase / セリンプロテアーゼ / Fas / GVHD, |
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| Research Abstract |
1) It has been said that freshly isolated human peripheral blood T (hPBT) cells are resistant to Fas-mediated apoptosis, because they are resistant to anti-Fas antibody treatment. However, we found that the Fas positive fraction of hPBT is killed by the membrane-bound form but not the soluble form of Fas ligand (FasL). While, hPBT activated by concanavalin A in vitro became sensitive to both membrane-bound and soluble FasL. Thus, FasL-sensitivity of T cells changes depending on a activation status of T cells, and that membrane-bond and soluble FasL may play distinctive roles in animals.
2) Using a murine models of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation, we demonstrated that both FasL and perforin, the major effector molecules of cytotoxic T lymphocytes, are involved in this disease, and that FasL rather than perforin was associated with lethality. Administration of FLIM58 reduced the weight loss and mortality caused by GVHD. Our results demonstrated that neutralizing agents for FasL are therapeutic for lethal GVHD.
3) We demonstrated that Fas ligand (FasL) introduced in tumor cells induces a massive infiltration of neutrophils, when the tumor cells are transplanted in peritoneal cavity of syngeneic mice. We also found that the FasL induces in inflammatory cells activation and release of IL-1β, which can explain the inflammatory activity of FasL. In addition, IL-1β converting enzyme (ICE), which is essential for LPS-induced IL-1β activation is not essential for the FasL-induced one. This activity was found to be mediated by membrane-bound but not natural soluble Fas ligand.
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