| Project/Area Number |
09253201
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
YOSHIKI Takashi Hokkaido University, School of Medicine, Professor, 医学部, 教授 (60220612)
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| Co-Investigator(Kenkyū-buntansha) |
SHIBATA Masahiko Hokkaido University, School of Medicine, Research Instructor, 医学部, 助手 (80301886)
IKEDA Hitoshi Hokkaido University, School of Medicine, Lecturer, 医学部, 講師 (20232192)
脇坂 明美 北海道大学, 医学部, 助教授 (90113646)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥21,000,000 (Direct Cost: ¥21,000,000)
Fiscal Year 1999: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 1998: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 1997: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | HTLV-I / ANIMAL MODELS / TRANSGENIC RATS / THYMOMA / COLLAGEN VASCULAR DISEASES / HAM / TSP / トランスジェニックラット / ウィルス発がん / 疾患モデル / ウイルス発がん |
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| Research Abstract |
To investigate the pathogenetic role of HTLV-I, we established three animal models for HTLV-I-related diseases and analyzed them. Results are described below.
(1) Transgenic rats with HTLV-I pX gene under cortrol of lck promoter (lck-pX rats) ;
We established 6 lines of lck-pX rats and epithelial thymomas developed in 4 of 6 lines. Positive correlation was observed between tumor occurrence in each line and levels of pX mRNA expression in their thymuses. The thymoma expressed pX mRNA at a high level and Tax protein was detected in the thymomacells. High levels of the pX mRNA expression was evident in thymic epithelial/stromal cells of lck-pX rats before developing thymoma. Bone marrow cell transfer from lck-pX rats to normal rats induced thymomas in the recipient rats. The thymomas in recipient rats expressed pX mRNA and Tax protein.
(2) Transgenic rats with HTLV-I LTR-env-pX gene (env-pX rats)
A number of collagen vascular diseases developed in env-pX rat. By reciprocal bone marrow and spl
… More
een cell transfer experiments, at least three pathogenetic roles of the transgene were indicated. Although oligoclonal T cell expansion was found in affected joints and skin lesions, common T cell clone and specific amino acid motif of TCRVβ CDR3 region were not evident in affected lesions among env-pX rats. Since arthritis in env-pX rats was easily induced by the inoculation of type II collagen, suggesting env-pX rats are states of immune hyper responsiveness. Pretreatment with spleen cells of normal rats suppressed development of all diseases in env-pX rats, including collagen-induced arthritis. Immune regulatory CD4+CD25+T cells in spleen of env-pX rats lost the temporal increment of those in a maturating period of normal spleen.
(3) HTLV-I-infected WKAH rats for a model of HAM/TSP (HAM rats) ;
Major infected cells in the spinal cords of HAM rats were micrccglia/macrophagelineage cells. Pathogenetic increment of the pX and TNF-α expression and suppression of the bcl-2 expression were observed before starting apoptosis of oligodendrocytes in spinal cords of HAM rats, but not in those of HAM resistant strains. The suppression of bcl-2 expression was specifically evident in oligodendorocytes of HAM rats, but not in microcgial cells of HAM rats. In vitro-separated oligodendrocytes from spinal cords of HAM rats were easily underwent apoptosis by addition of cytotoxic factors compared with that of HAM resistant strains and uninfected WKAH rats. Less
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