PATHOGENETIC ROLE OF HTLV-I IN ANIMAL MODELS FOR HTLV-l-RELATED DISEASES

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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