HAMの臨床病態・発症機序の解明並びに新治療法の開発に関する研究

阐明HAM临床病理和发病机制并开发新疗法的研究

• 批准号: 11470146
• 负责人: OSAME Mitsuhiro
• 金额: $ 9.15万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470146/
• 关键词: HAM occurrence; Analysis of Genetic Factors; Analysis of Viral Factors; ROC curve; Candidate Gene Analysis; Tax subtype; non-HLA factors; Regression Analysis; HAM; HTLV-Iキャリア; HLA classI; HLA classII; プロウイルス量; 細胞傷害性T細胞; HTLV-Iプロウイルス量; PCR定量

We have analyzed the genetic and viral background of the pathological mechanism of HTLV-I associated myelopathy HAM and have followed up more than 300 patients of HAM and at least 64 patients more than 10 years.For genetic background, we have found that HLA-A【thermodynamics】02 and HLA-Cw【thermodynamics】08 have conferred protection to be HAM and HLA-B【thermodynamics】5401 and HLA-DRB1【thermodynamics】0101 predisposition to the disease. To further clarify the relation between HTLV-I proviral load and these factors, we have tried to determine the cut off value that can distinguish the patients with HAM and HTLV-I infected healthy individuals. For this purpose, we have used ROC curve and been able to show that the viral load of 2 % of peripheral blood mononuclear cells is good for differentiate these two groups with more than 80 % specificity and BOX sensitivity. On dividing HAM patient group and carrier group by using this 2 % viral load, we have been able to show the difference of genetic … More background at the different viral load. HLA-A【thermodynamics】02 and HLA-DRB1【thermodynamics】0101 have shown the genetic effect at the low viral load and HLA-B【thermodynamics】5401 at high viral load. This may be due to the different host response at the different environment such as virus effect. From the regression analysis, we have shown that it may be possible to predict HAM or not more than 80 % accuracy in our cohort by using the above mentioned factors.We have further analyzed non-HLA genetic factors by candidate gene analysis and have been able to find predisposing or protective factors to the disease. THF-a (-863A) allele have shown predisposing effect at-the high viral load, SDF-1-801A 3'UTR have decreased the risk to be HAM and IL-15 191C allele have had effect to decrease the viral load. Including these factors to the regression analysis, we have been able to predict 88 % cases of HAM.From the viral factor analysis, we have found HTLV-I tax A subtype that had predisposing effect to HAM. Since this tax A subtype prevails more in Caribbean area, this may explain high frequency to be HAM from HTLV-I carriers. We have also analyzed adhesion molecules and found that CD44 splice v6/v10 existed more frequently on the lymphocytes from patients with HAM than carriers. Less

我们分析了HTLV-I相关性脊髓病HAM发病机制的遗传和病毒背景，并对300多名HAM患者和至少患者进行了10多年的随访。对于遗传背景，我们发现HLAA[热力学]02和HLACW[热力学]08对HAM具有保护作用，而HLAB[热力学]5401和HLADRB1[热力学]0101是HAM的易感基因。为了进一步阐明HTLV-I前病毒载量与这些因素的关系，我们试图确定能够区分HAM患者和HTLV-I感染健康人的临界值。为此，我们使用ROC曲线，并能够证明2%的外周血单个核细胞的病毒载量对区分这两组具有80%以上的特异性和盒敏感性。用这2%的病毒载量划分HAM患者组和携带者组，我们已经能够显示出基因…的差异更多关于不同病毒载量的背景知识。人类白细胞抗原-A[热力学]02和人类白细胞抗原-DRB1[热力学]0101在低病毒载量时表现出遗传效应，而在高病毒载量时则表现出遗传效应。这可能是由于宿主对不同环境的反应不同，如病毒作用等。回归分析表明，上述因素对本组人群HAM的预测准确率可达80%以上，并通过候选基因分析对非HLA型遗传因素进行了进一步分析，找到了HAM的易感因素或保护性因素。THF-a(-863A)等位基因在高病毒载量时具有易感作用，SDF-1-801a 3‘非编码区降低HAM的风险，IL-15 191C等位基因具有降低病毒载量的作用。将这些因素纳入回归分析，我们已经能够预测88%的HAM病例。从病毒因素分析中，我们发现HTLV-I Tax A亚型对HAM有易感作用。由于这种税A亚型在加勒比海地区更流行，这可能解释了HTLV-I携带者火腿频率高的原因。我们还分析了黏附分子，发现CD44剪接V6/V10在HAM患者的淋巴细胞上比携带者更常见。较少

项目成果

Jeffery KJ, Siddiqui AA, Bunce M, Lloyd AL, Vine AM, Witkover AD, Izumo S, Usuku K, Welsh KI, Osame M, Bangham CR.: "The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection"J Immunol.. 165

Jeffery KJ、Siddiqui AA、Bunce M、Lloyd AL、Vine AM、Witkover AD、Izumo S、Usuku K、Welsh KI、Osame M、Bangham CR.：“HLA I 类等位基因和杂合性对人类 T 结果的影响

Matsuzaki T, Nakagawa M, Nagai M, Nobuhara Y, Usuku K, Higuchi I, Takahashi K, Moritoyo T, Arimura K, Izumo S, Akiba S, Osame M.: "HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) with amyotrophic lateral sclerosis-like manifestations

Matsuzaki T、Nakakawa M、Nagai M、Nobuhara Y、Usuku K、Higuchi I、Takahashi K、Moritoyo T、Arimura K、Izumo S、Akiba S、Osame M.：“HTLV-I 相关脊髓病 (HAM)/热带痉挛

Jeffery KJ,et al.: "HLA alleles determine human T-lymphotropic virus-I (HTLV-I)proviral load and the risk of HTLV-I-associated myelopathy"Proc Natl Acad Sci USA. 96(7). 3848-3853 (1999)

Jeffery KJ 等人：“HLA 等位基因决定人类 T 淋巴细胞病毒-I (HTLV-I) 前病毒载量和 HTLV-I 相关脊髓病的风险”Proc Natl Acad Sci USA。

Jeffery KJ, et al.: "The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection."Journal of Immunology. 165. 7278-7284 (2000)

Jeffery KJ 等人：“HLA I 类等位基因和杂合性对人类 T 细胞嗜淋巴细胞病毒 I 型感染结果的影响。”免疫学杂志。

Bangham CR.,et al.: "Genetic control and dynamics of the cellular immune response to the human T-cell leukaemia virus,HTLV-I."Philos Trans R Soc Lond B Biol Sci. 354(1384). 691-700 (1999)

Bangham CR. 等人：“人类 T 细胞白血病病毒 HTLV-I 细胞免疫反应的遗传控制和动态。”Philos Trans R Soc Lond B Biol Sci。