Exploitation of new therapies for HTLV-I-assotiated myelopathy

HTLV-I 相关脊髓病新疗法的开发

基本信息

批准号：
14207031
负责人：
OSAME Mitsuhiro
金额：
$ 23.71万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207031/
关键词：
HTLV-I-associated myelopathy HTLV-I proviral load Therapy Prognosis metalloproteinase inhibitor susceptible genes cytotoxic T lymphocytes 予後判定 dN dS比治療薬開発高齢発症 MMP MMP阻害剤 HTLM-Iプロウイルス量

项目摘要

In this research project, we have deeply improved our understanding for the pathogenesis of HTLV-I-associated myelopathy(HAM) and developed a hopeful therapy for the disease. It is an initial event that HTLV-I-infected cells infiltrate into the central nervous system for the development of HAM, where matrix metalloproteinase(MMP)-2 and -9 play an important role. We found that a selective MMP inhibitor specific for MMP-2 and -9, N-Biphenyl sulfonyl-phenylalanine hydroxamic acid(BPHA), significantly inhibited migration activity of CD4+ T lymphocytes (which are a main reservoir of HTLV-I) from HAM patients. This suggests that the compound is a candidate for a new therapy for HAM patients. We had identified many genetic factors which increase susceptibility for the disease, and we newly identified two genetic factors, polymorphism of interleukin-10 promoter, and the length of tandem repeat in MMP-9 promoter. Using these host genetic factors, we made a formula to predict the risk of the development of HAM. When we utilized it for HTLV-I asymptomatic carriers, the carriers with high risk values showed faint abnormalities on the neurological examination, suggesting that the formula is very useful for prediction of the prognosis. In a genetic analysis of HTLV-I, the ratio of non-synonymous change to synonymous change (dN/dS ratio) of HTLV-I gene was lower in HAM patients than in HTLV-I carriers, implying that viral replication is more effectively inhibited in HAM patients than in the carriers. Moreover, HAM patients with HLA-A^*02 had lower dN/dS ratio than those without HLA-A^*02, suggesting that HL-A^*02 has an inhibitory effect on viral replication. Additionally, an analysis of dN/dS ratio, cytotoxic T lymphocytes(CTL) epitopes and frequency of mutant virus demonstrated that CTL had antiviral pressure in vivo, however, a mutant virus did not predominate. Further studies are needed to establish a more effective therapy for HAM patients.

在该研究项目中，我们深入提高了对HTLV-I相关性脊髓病（HAM）发病机理的理解，并为该疾病开发了一种希望的疗法。首先，HTLV-I感染的细胞浸润到中枢神经系统中以开发HAM，其中基质金属蛋白酶（MMP）-2和-9起重要作用。我们发现，针对MMP-2和-9，N-双苯基磺酰基 - 苯丙氨酸羟氨酸（BPHA）的选择性MMP抑制剂（BPHA）显着抑制了CD4+ T型淋巴细胞的迁移活性（这是HAM患者HTLV-I的主要储层）。这表明该化合物是针对HAM患者进行新疗法的候选者。我们已经确定了许多遗传因素，这些因素增加了对疾病的敏感性，我们新发现了两个遗传因素，白介素-10启动子的多态性以及MMP-9启动子中串联重复的长度。使用这些宿主遗传因素，我们制定了一个公式来预测HAM发展的风险。当我们将其用于HTLV-I无症状载体时，具有高风险值的载体在神经系统检查中表现出微弱的异常，这表明该配方对于预测预后非常有用。在对HTLV-I的遗传分析中，HAM患者的HTLV-I基因的非同义变化与HTLV-I基因的同义变化（DN/DS比）的比率低于HTLV-I载体，这意味着与HAM患者相比，HAM患者在HAM患者中更有效地抑制了病毒复制。此外，HLA-A^*02的HAM患者的DN/DS比低于没有HLA-A^*02的患者，这表明HL-A^*02对病毒复制具有抑制作用。此外，对DN/DS比，细胞毒性T淋巴细胞（CTL）表位和突变病毒频率的分析表明，CTL在体内具有抗病毒压力，但是，突变病毒并未占主导性。需要进一步的研究来为HAM患者建立更有效的疗法。