| Project/Area Number |
13470206
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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 |
Hematology
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| Research Institution | Ehime University |
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Principal Investigator |
YASUKAWA Masaki Ehime University Faculty of Medicine, Associate Professor, 医学部, 助教授 (60127917)
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| Co-Investigator(Kenkyū-buntansha) |
YAKUSHIJIN Yoshihiro Ehime University Faculty of Medicine, Instructor, 医学部, 助手 (30294797)
ABE Yasuhito Ehime University Faculty of Medicine, Associate Professor, 医学部, 助教授 (30184229)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2002: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 2001: ¥8,100,000 (Direct Cost: ¥8,100,000)
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| Keywords | Cancer antigens / Immunotherapy / Leukemia / Cytotoxic T lymphocytes / HLA / WT1 / Telomerase / HLA-A24 / 肺がん / 自殺遺伝子 |
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| Research Abstract |
To identify the novel cancer-associated antigens and to develop the novel immunotherapy for hematological malignancies, this study was performed. The data obtained from the series of experiments are as follows.
1) A WT1-specific, HLA-A24-restricted CTL clone (designated TAK-1) exhibited cytotoxicity against lung cancer cell lines bearing HLA-A24 but did not lyse cells lacking this HLA. Adoptive transfer of TAK-1 into nude mice that had been engrafted with an HLA-A24-positive lung cancer cell line resulted in inhibition of the cancer cell growth and prolonged survival. These findings strongly suggest that WT1 is a universal tumor-associated antigen and that WT1 -targeting immunotherapy offers a potentially effective treatment option for lung cancer as well as leukemia.
2) A novel WT1-derived peptide-specific CD8^+ CTL line, designated NIM-1 was established. NIM-1 lysed HLA-A24-positive leukaemia cells, but not HLA-A24 negative leukaemia cells or normal cells.
3) Immature dendritic cells (D
… More
Cs) were loaded with leukemia cells with t(6 ; 9) or t(9 ; 22) and then cocultured with the dek-can fusion peptide-specific or the bcr-abl fusion peptide-specific CD4^+ T-lymphocyte clone. The dek-can peptide-specific and bcr-abl peptide-specific CD4^+ T-lymphocyte clones produced interferon-γ(IFN-γ) when they were cocultured with HLA-DR-matched but not with mismatched DCs which had been loaded with apoptotic as well as necrotic leukemia cells with t(6 ; 9) and t(9 ; 22), respectively. These data indicate that the acute myelogenous leukemia-associated fusion protein, dek-can, and chronic myelogenous leukemia-associated fusion protein, bcr-abl, are both processed and presented by DCs to the fusion peptide-specific CD4^+ T lymphocytes.
4) In order to clarify the roles of perforin in antigen-specific cytotoxicity mediated by human CD4^+ CTLs, antigen-specific human CD4^+ T-lymphocyte clones were established from a patient with hereditary perforin deficiency and their cytotoxic activities were investigated. The data demonstrated that perforin-negative CD4^+ CTLs can exert cytotoxicity against Fas-sensitive target cells ; however, perforin plays essential roles in antigen-specific cytotoxicity mediated by human CD4^+ as well as CD8^+ CTLs. Less
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