ANALYSIS OF HTLV-I PATHOGENICITY USING ANIMAL MODELS

为探讨htlv - 1相关疾病的发病机制，采用htlv - 1感染或转基因技术建立了htlv - 1相关免疫紊乱的大鼠模型：HAM大鼠（HAM/TSP）、htlv - 1致瘤性乳腺癌发展为pX大鼠（乳腺癌发展为pX大鼠）和自身免疫性疾病发展为env-pX大鼠（htlv - 1相关免疫紊乱）。1) HAM大鼠：HTL-I感染WKAH大鼠脊髓中，感染后9个月开始的少突胶质细胞凋亡是脱髓鞘发生前的第一个组织病理学事件。pX在病变组织中选择性表达，而在其他组织中不表达，尽管原病毒dna一致被鉴定出来。tnf - α在病变病灶中频繁表达。感染后7个月，靶病变组织中均有pX和tnf - α的表达。综上所示，靶病变中髓磷脂形成细胞通过pX的选择性活化和/或TNF-alp的产生而发生凋亡死亡，是HAM大鼠疾病的主要发病途径。2) pX大鼠：在小鼠H-2启动子调控下携带pX基因的转基因大鼠，5月龄开始发生未分化伴粒细胞浸润的乳腺癌。pX和宿主基因Gro和MIP-2 mrna在肿瘤组织中均有高表达。由于几种癌基因和抗癌基因的表达和点突变未被证实，因此在这些pX大鼠中可能激活了迄今尚未发现的新的致癌途径。3) env-pX大鼠：建立携带env-pX基因的转基因大鼠，在自身LTR控制下。从5周龄开始，env-pX大鼠出现类似RA的关节炎、类似PN的坏死性动脉炎、多发性肌炎、心肌炎和干燥综合征样的唾液和流泪腺炎。胸腺萎缩伴CD4CD8阳性胸腺细胞严重缺失。血清中检测到自身抗体，包括类风湿因子、抗dsdna和抗心磷脂抗体。有证据表明HTLV-I env-pX基因可能引起这些具有自身免疫性现象的免疫紊乱。少

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 … More 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