Induction of chronic inflammatory myelopathy in rats infected with recombinant HTLV-I

人类T淋巴细胞病毒1型(HTLV-I)与HTLV相关性脊髓病(HAM)、关节炎、葡萄膜炎和支气管炎密切相关。HTLV-I感染引起的免疫学改变可能会影响病情，但其发病机制尚不清楚。为了阐明这些疾病的发病机制，建立动物模型是很重要的。虽然已有报道通过实验性感染HTLV-I诱导WKA大鼠发生Ham样瘫痪，但在这些动物中既没有观察到炎症变化，也没有观察到免疫反应的改变。此外，HTLV-I转基因小鼠或大鼠可诱发类风湿性关节炎(RA)样而非HAM样骨髓病变。其中一株(福氏株)接种于WKA大鼠可引起类风湿性关节炎。另一方面，当ATL患者来源的HTLV感染的T细胞株MT-2接种到WAK大鼠后，WAK大鼠发生了髓神经病。这些发现表明，临床表达在一定程度上取决于接种的HTLV感染细胞系。最近，在技术上使HTLV-I的感染性cDNA克隆成为可能。因此，我们试图分别从MT-2细胞和Fuk细胞中克隆感染性基因，以阐明HTLV-I基因组的哪一部分在脊髓病或关节炎的诱导中起关键作用。我们对MT-2和Fuk株的HTLV-I前病毒DNA进行了测序，发现在来源于Fuk细胞的HTLV-I的Px区有几个产生氨基酸替换的突变。目前正在对各细胞系进行HTLV-I感染性cDNA克隆。

Human T-lymphotropic virus type 1 (HTLV-I) is closely linked to HTLV-associated myelopathy (HAM), arthritis, uveitis and bronchial alveolitis. Immunological changes caused by HTLV-I infection may affect the condition, but the pathomechanism remains unknown. To elucidate the pathomechanism of these diseases, it is important to make animal models. Although induction of HAM-like paraparesis through experimental infection of WKA rats with HTLV-I has been reported, neither inflammatory changes nor alteration of the immune response has been observed in these animals. In addition, HTLV-I transgenic mice or rat has been reported to induce rheumatoid arthritis (RA)-like but not HAM-like myelopathy.We established many HTLV-infected T cell lines from HAM patients. One of them (Fuk line) inoculated to WKA rat caused RA-like arthritis. On the other hand, when MT-2, which is a HTLV-infected T cell line derived from ATL patient, was inoculated to WAK rats, they developed myeloneuropathy. These findings suggest that clinical expression in part depends on the HTLV-infected cell lines inoculated. Recently, it becomes technically possible to make infectious cDNA clones of HTLV-I. So, we tried to make infections cDNA clones from MT-2 cells and Fuk cells, respectively, to clarify which portion of HTLV-I genome play a pivotal role for the induction of myelopathy or arthritis. We sequenced the HTLV-I proviral DNA of MT-2 and Fuk line and found several mutations producing amino acid substitution in the pX region of HTLV-I derived from Fuk cells. It is now underway to make infections cDNA clone of HTLV-I of each cell lines.