| Project/Area Number |
12557081
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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 |
Hematology
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| Research Institution | Ehime University |
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Principal Investigator |
YASUKAWA Masaki Ehime University Faculty of Medicine, First Department of Internal 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, First Department of Internal Medicine, Instructor, 医学部, 助手 (30294797)
SAKAI Ikuya Ehime University Faculty of Medicine, First Department of Internal Medicine, Instructor, 医学部, 助手 (10205700)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | Leukemia / Malignant lymphoma / Immunotherapy / Gene therapy / Cytotoxic T lymphocytes / 造血器腫瘍 / 細胞免疫療法 / WT1 / テロメラーゼ / 細胞障害性T細胞 / 自殺遺伝子 / 不死化細胞 / HLA / hTERT |
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| Research Abstract |
This study was performed to develop the novel immunotherapy for hematological malignancies. The data obtained from the series of experiments are as follows.
1) 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.
2) 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.
3) Immature dendritic cells (DCs) were loaded with leukemia cells with t(6 ; 9) or t
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(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 perform 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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