Grant-in-Aid for Scientific Research on Priority Areas.
|Allocation Type||Single-year Grants|
|Research Institution||HOKKAIDO UNIVERSITY|
YOSHIKI Takashi Hokkaido University, School of Medicine, Professor, 医学部, 教授 (60220612)
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)
|Project Period (FY)
1997 – 1999
Completed(Fiscal Year 2000)
|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)
|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|
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
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