Analysis of HTLV-I-Associated Diseases using Animal Models

为了探讨HTLV-I在HTLV-I相关疾病(包括ATL、HAM/TSP、关节病等)的发病机制中的作用，我们分析了HTLV-I感染HAM/TSP大鼠(HAM大鼠)模型。脊髓内感染细胞以小胶质细胞/巨噬细胞为主，无症状早期可见前病毒扩张和Px表达增加。在小胶质细胞/巨噬细胞中表达编码于Px区的Tax反式激活肿瘤坏死因子-α的产生，而肿瘤坏死因子-α诱导少突胶质细胞凋亡，下调bcl2的表达，从而发生脱髓鞘。作为清除剂的活化的小胶质细胞/巨噬细胞的渗透和增殖也进行了脱髓鞘。在晚期，星形胶质细胞在局部增殖以修复损伤。2)建立HTLV-I型LTR-env-Px转基因大鼠模型，建立Colla…更多的遗传性血管疾病(env-px大鼠)：在env-px大鼠，在体外和体内观察到淋巴细胞免疫高反应性和免疫调节T细胞功能障碍。骨髓、脾和胸腺的细胞或组织移植实验结果表明，三种不同的机制与env-px大鼠的疾病发生有关。在胸腺中表达的转基因是发生血管炎的原始基因，而在外周淋巴细胞中表达的转基因是发生皮炎的原始基因。当靶组织拥有转基因时，关节炎和其他疾病就会发生。3)p561CK1型启动子控制下携带PX基因的转基因大鼠模型发生胸腺瘤(LCK-PX大鼠)：胸腺瘤的发生率与转基因表达水平相关。胸腺瘤由髓上皮细胞发展而来，细胞来源于非贴壁的骨髓单个核细胞。较少

To investigate the pathogenetic roles of HTLV-I to develop HTLV-I-associated diseases, including ATL, HAM/TSP, arthropathy and others, we analyzed rat models, which were previously established by the infection or transgene of HTLV-I.1) An HTLV-I infected rat model for HAM/TSP (HAM rat) : In this project, we clarified the pathogenetic role of HTLV-I in HAM rat. Majority of infected cells in the spinal cords is microglia/macrophages and the provirus expansion and increase of pX expression are observed at early asymptmatic stage. Expression of Tax, encoded in pX region, in microglia/macrophages transactivates TNF-α production, and TNF-α induces apoptosis of oligodendrocytes with down-regulation of bcl-2, then demyelination develops. Infiltration and proliferation of activated microglia/macrophages as a scavenger are also progressed demyelination. At the late stage, astrocytes proliferate locally to repair the damage in the lesion.2) An HTLV-I LTR-env-pX transgenicrat model developed colla … More gen vascular diseases (env-pX rat) : In env-pX rats, in vitro and in vivo immune hyper-responsiveness of lymphocytes and dysfunction of immune regulatory T cells were observed. Results of cell or tissue transfer experiments of bone marrow, spleen and thymus suggest that three different mechanisms relate to develop diseases of env-pX rats. The transgene expressed in thymus is primitive to develop the vasculitis, and that in peripheral lymphocytes is to develop dermatitis. Arthritis and other diseases develop when the target tissues possess the transgene. On the other hand, HAM rat like encephalomyelopathy develops in one of two env-pX rat lines after linebreeding in closed colony.3) A transgenic rat model carrying pX under the control of p561ck type 1 promoter developed thymoma (lck-pX rat) : Frequency of thymomas was correlated with expression levels of the transgene. The thymoma develops from medullary epithelial cells and the cells were originated from non-adherent mononuclear cells of bone marrow. Less