|Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1995: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1994: ¥5,300,000 (Direct Cost: ¥5,300,000)
To investigate the pathogenesis of HTLV-I associated diseases, three rat models, HAM rat for HAM/TSP,mammary carcinoma developed pX rat for HTLV-I tumorigenicity, and autoimmune diseases developed env-pX rat for HTLV-I associated immunological disorders, were established by HTLV-I infection or transgenic technique.
1) HAM rat : In the spinal cords of WKAH rats carrying HTL-I infection, the apoptotic death of oligodendrocytes starting at 9 months after the infection was the first histopathological event before the demyelination. pX was selectively expressed in the diseased leasions, but not in others, even though provirus DNAs were consistently identified. TNF-alpha were frequently expressed in the diseased lesions. Moreover, both pX and TNF-alpha were expressed in the target leasions from 7 months after the infection. The collective evidence suggests that the apoptotic death of myelin forming cells in the target leasions by the selective activation of pX,and/or the production of TNF-alp
ha is a major pathogenetic pathway of HAM rat disease.
2) pX rat : In transgenic rats carrying the pX gene under control of the mouse H-2 promoter, undifferentiated mammary carcinomas with granulocytic infiltration developed starting at 5 months of age. mRNAs of both pX and host genes, Gro and MIP-2, were highly expressed in the tumor tissue. Since expression and point mutation of several oncogenes and anti-oncogene were not demonstrated, hitherto unidentified novel oncogenic pathways may be activated in these pX rats.
3) env-pX rat : Transgenic rats carrying the env-pX gene, under control of own LTR,were established. Starting at 5 weeks of age, arthritis resembling RA,necrotizing arteritis resembling PN,polymyositis, myocarditis and Sjogren's syndrome-like sialo-and dacryoadenitis developed in env-pX rats. Thymic atrophy with severe depletion of CD4CD8 positive thymocytes was also observed. Autosntibodies, including rheumatoid factors and anti-dsDNA and anti-cardiolipin antibodies, were detected in the serum. The evidence indicztes that HTLV-I env-pX gene may cause these immunological disorders with autoimmune phenomenon. Less