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

为了探讨HTLV-I的致病作用，我们建立了三种HTLV-I相关疾病的动物模型并对其进行了分析。结果如下：(1)在lck启动子控制下转HTLV-I px基因的大鼠(lck-px大鼠)，建立了6个lck-px大鼠系，其中4个系发生了上皮性胸腺瘤。各株系肿瘤发生率与胸腺Px基因表达水平呈正相关。胸腺瘤高水平表达Px基因，在胸腺细胞中检测到Tax蛋白。在胸腺瘤发生前，LCK-PX大鼠胸腺上皮/间质细胞中PX基因的表达水平明显升高。LCK-PX大鼠骨髓细胞移植给正常大鼠诱发受体大鼠胸腺瘤。受体大鼠胸腺瘤组织中表达Px基因和Tax蛋白。(2)转HTLV-I LTR-env-Px基因大鼠(env-px大鼠)在env-px大鼠体内发生了大量的胶原血管病变。移植骨髓和Spl-…在更多的细胞转移实验中，至少表明了转基因的三种致病作用。虽然在病变关节和皮损中发现了T细胞的寡克隆性增殖，但在环孢素PX大鼠的皮损中，TCRVCDR3区的共同T细胞克隆和特异性氨基酸基序并不明显。由于ENV-PX大鼠接种II型胶原容易诱发关节炎，提示ENV-PX大鼠处于免疫高反应状态。用正常大鼠的脾细胞进行预处理可抑制env-px大鼠所有疾病的发展，包括胶原性关节炎。ENV-PX大鼠脾内免疫调节性CD4+CD25+T细胞失去正常脾成熟期的时间增量。(3)HTLV-I感染WKAH大鼠为HAM/TSP模型(HAM大鼠)，HAM大鼠脊髓内主要感染细胞为微胶质/巨噬细胞系细胞。HAM大鼠脊髓少突胶质细胞开始凋亡前，Px和肿瘤坏死因子-α表达增加，bcl2表达抑制，而HAM耐药大鼠未见此现象。BCL-2的表达在HAM大鼠的少突胶质细胞中有特异性的抑制，而在HAM大鼠的微血管细胞中无明显的抑制作用。与HAM耐药株和未感染WKAH大鼠相比，HAM大鼠体外分离的脊髓少突胶质细胞在加入细胞毒性因子后容易发生凋亡。较少

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