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

HTLV-I 在 HTLV-1 相关疾病动物模型中的致病作用

基本信息

批准号：
09253201
负责人：
YOSHIKI Takashi
金额：
$ 13.44万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

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

为了研究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。(1)lck启动子(lck-)控制下的HTLV-I pX基因转基因大鼠。 pX大鼠)；我们建立了6个系的lck-pX大鼠，并且在6个系中的4个系中观察到每个系中的肿瘤发生与其pX mRNA表达水平之间存在正相关性。胸腺瘤表达高水平的 pX mRNA，并且在胸腺瘤细胞中检测到高水平的 pX mRNA 表达，然后从 lck 进行骨髓细胞转移。 -pX大鼠向正常大鼠诱导受体大鼠胸腺瘤，受体大鼠胸腺瘤表达pX mRNA和Tax蛋白。(2)转基因大鼠。 HTLV-I LTR-env-pX 基因（env-pX 大鼠）在 env-pX 大鼠中发生多种胶原血管疾病。通过相互骨髓和 spl … More een 细胞转移实验，转基因的至少三种致病作用被证实。尽管在受影响的关节和皮肤病变中发现了寡克隆 T 细胞扩增，但在 env-pX 中受影响的病变中，常见的 T 细胞克隆和 TCRVβ CDR3 区域的特定氨基酸基序并不明显。由于接种 II 型胶原很容易诱发 env-pX 大鼠的关节炎，表明用正常大鼠的脾细胞预处理 env-pX 大鼠可抑制 env-pX 大鼠所有疾病的发展。包括胶原诱导的关节炎 env-pX 大鼠脾脏中的免疫调节性 CD4+CD25+T 细胞失去了正常成熟期的时间增量。 (3)HTLV-I感染WKAH大鼠HAM/TSP模型(HAM大鼠);HAM大鼠脊髓主要感染细胞为小胶质细胞/巨噬细胞系细胞pX和TNF-α表达的致病性增加。 HAM 大鼠脊髓少突胶质细胞凋亡前观察到 bcl-2 表达抑制，但 HAM 耐药大鼠脊髓中未观察到 bcl-2 表达抑制bcl-2 表达的抑制在 HAM 大鼠的少突胶质细胞中特别明显，但在 HAM 大鼠的小胶质细胞中则不然。与添加细胞毒性因子相比，体外分离的 HAM 大鼠脊髓少突胶质细胞更容易发生凋亡。 HAM 抗性品系和未感染的 WKAH 大鼠的数量较少。