Analysis of HTLV-I-Associated Diseases using Animal Models

为了研究HTLV-I在发生HTLV-I相关疾病（包括ATL、HAM/TSP、关节病等）中的致病作用，我们分析了先前通过HTLV-I感染或转基因建立的大鼠模型。1）HAM/TSP的HTLV-I感染大鼠模型（HAM大鼠）：在本项目中，我们阐明了HTLV-I在HAM大鼠中的致病作用。脊髓中的大多数感染细胞是小胶质细胞/巨噬细胞，并且在早期无症状阶段观察到前病毒扩增和pX表达增加。Tax基因在小胶质细胞/巨噬细胞中的表达可反式激活TNF-α的产生，TNF-α可诱导少突胶质细胞凋亡并下调bcl-2的表达，从而导致脱髓鞘。作为清道夫的活化的小胶质细胞/巨噬细胞的浸润和增殖也进行脱髓鞘。在晚期，星形胶质细胞局部增殖以修复损伤。2）HTLV-I LTR-env-pX转基因大鼠模型产生胶原蛋白， ...更多信息 生殖血管疾病（env-pX大鼠）：在env-pX大鼠中观察到淋巴细胞的体外和体内免疫高反应性和免疫调节性T细胞的功能障碍。骨髓、脾脏和胸腺的细胞或组织移植实验结果表明，env-pX大鼠疾病的发生与三种不同的机制有关。胸腺中表达的转基因是发生血管炎的原始基因，外周血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。另一方面，HAM大鼠样脑脊髓病在两个env-pX大鼠系中的一个系中在封闭的群体中线性繁殖后发生。3）携带pX的转基因大鼠模型在p561 ck 1型启动子的控制下发生胸腺瘤（lck-pX大鼠）：胸腺瘤的频率与转基因的表达水平相关。胸腺瘤是由髓质上皮细胞发展而来，而这些细胞是由骨髓的非贴壁单个核细胞发展而来。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