Role of HLA Class II Genes in Demyelination

HLA II 类基因在脱髓鞘中的作用

基本信息

批准号：
8036554
负责人：
CHELLA S DAVID
金额：
$ 34.5万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8036554
关键词：
Adverse effects Affect Affinity Alleles Anti-Inflammatory Agents Anti-inflammatory Antigens Autoantigens Autoimmune Diseases Autoimmunity Avidity CD4 Positive T Lymphocytes Cells Chronic Data Demyelinating Diseases Demyelinations Development Disease Disease Outcome Disease Resistance Disease susceptibility Encephalomyelitis Etiology Evolution Experimental Autoimmune Encephalomyelitis Experimental Models Frequencies Future Gene Conversion Generations Genes Genetic Genetic Polymorphism Granulocyte-Macrophage Colony-Stimulating Factor HLA-DQ Antigens HLA-DQ8 antigen HLA-DR Antigens Haplotypes Human IL17 gene Immune response Immune system Incidence Infection Inflammatory Interleukin-17 Link Linkage Disequilibrium MHC Class II Genes Malignant - descriptor Mediating Modeling Multiple Sclerosis Mus Mutation Pathogenesis Patients Peptide Vaccines Peptide/MHC Complex Phenotype Play Population Population Study Predisposition Process Production Protocols documentation Relative (related person)Relative Risks Resistance Role Severities Shapes Simulate T-Lymphocyte Therapeutic Transgenic Mice Translational Research base central nervous system demyelinating disorder cytokine drug development insight novel therapeutics novel vaccines protective effect public health relevance research and development research study

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease has both a genetic and an environmental predisposition. Among all the genetic factors associated with MS susceptibility, HLA-class II haplotypes such as DR2/DQ6, DR3/DQ2, DR4/DQ8, show the strongest association. Although a direct role of HLA-DR alleles in MS have been confirmed, it has been difficult to understand the contribution of HLA-DQ alleles in disease pathogenesis, due to strong linkage disequilibrium. Population studies have indicated that DQ alleles may play a modulatory role in progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we generated single and double transgenic mice expressing HLA class II genes and lacking endogenous mouse class II genes. Previously, we have shown that HLA-DR3 transgenic mice were susceptible to PLP91-110 induced EAE, while DQ6 (DQB1*0601) and DQ8 (DQB1*0302) transgenic mice were resistant. Surprisingly DQ6/DR3 double transgenic mice were resistant while DQ8/DR3 mice showed higher disease incidence and severity. Protective effect of DQ6 in DQ6/DR3 mice was mediated by anti-inflammatory IFN3, while disease exacerbating effect of DQ8 molecule was mediated by IL17. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS. This proposal is aimed to enhance understanding of the mechanism by which epistatic interactions between HLA-DQ and -DR molecules determine the susceptibility vs. resistance to disease. We are proposing two aims to understand the mechanism by which HLA-DQ molecule modulate the disease outcome in HLA-DR/DQ double transgenic mice. In the first aim, we will examine how HLA-DQ8 molecule increases disease incidence and severity in DQ8/DR3 double transgenic mice by analyzing- i) role of HLA polymorphism and peptide-MHC affinity/avidity in generation of pro-inflammatory IL17 production from DQ8 restricted CD4 T cells; ii) mechanism by which IL17 cause increased encephalitogenicity in DR3DQ8 mice; and iii) role of GM-CSF produced by DQ8 restricted CD4 T cells in exacerbation of EAE in DR3DQ8 double transgenic mice. In the second aim, we will investigate how HLA-DQ6 restricted immune response leads to generation of high IFN3 producing regulatory CD4+ T cells, especially the role of MHC-peptide affinity/functional avidity. Next we will analyze mechanisms by which DQ6 restricted CD4+ T cells suppress EAE in HLA-DR3/DQ6 double transgenic mice. We will also generate a triple transgenic mice expressing disease susceptible HLA-DR3, disease protective -DQ6, and disease enhancing -DQ8 gene to simulate human heterozygous condition. The comprehensive studies outlined in this proposal should yield an insight into mechanism by which HLA class II molecules shape the T cell repertoire and regulate the pro-inflammatory and anti-inflammatory cytokine profile. This will facilitate the translational research development of novel therapeutic to treat inflammatory disease such as MS. PUBLIC HEALTH RELEVANCE: Although HLA haplotypes are linked to predisposition and onset of multiple sclerosis, it has been difficult in past to define a clear role of HLA molecule(s) in MS. We have used HLA transgenic mice successfully to understand their role in inflammatory and demyelinating disease of CNS such as MS using an experimental model experimental autoimmune encephalomyelitis (EAE). These humanized class II model of EAE can be used to evaluate potential therapeutic protocols and peptide vaccines applicable in the future to MS patients.

描述（由申请人提供）：多发性硬化症（MS）是一种炎症性脱髓鞘性自身免疫性疾病，具有遗传和环境倾向。在与 MS 易感性相关的所有遗传因素中，HLA II 类单倍型（例如 DR2/DQ6、DR3/DQ2、DR4/DQ8）显示出最强的关联。尽管HLA-DR等位基因在MS中的直接作用已被证实，但由于强连锁不平衡，很难理解HLA-DQ等位基因在疾病发病机制中的贡献。人群研究表明 DQ 等位基因可能在 MS 的进展中发挥调节作用。为了更好地了解 HLA-DR 和 -DQ 基因导致 MS 易感性和抗性的机制，我们生成了表达 HLA II 类基因但缺乏内源性小鼠 II 类基因的单转基因小鼠和双转基因小鼠。此前，我们已经证明HLA-DR3转基因小鼠对PLP91-110诱导的EAE敏感，而DQ6 (DQB1*0601)和DQ8 (DQB1*0302)转基因小鼠具有抗性。令人惊讶的是，DQ6/DR3 双转基因小鼠具有耐药性，而 DQ8/DR3 小鼠则表现出更高的疾病发生率和严重程度。 DQ6 对 DQ6/DR3 小鼠的保护作用是由抗炎 IFN3 介导的，而 DQ8 分子的疾病加重作用是由 IL17 介导的。基于这些观察，我们假设 HLA-DR 和 -DQ 基因之间的上位相互作用在 MS 易感性中发挥重要作用。该提案旨在加深对 HLA-DQ 和 -DR 分子之间的上位相互作用决定疾病易感性与抗性的机制的理解。我们提出两个目标，以了解 HLA-DQ 分子调节 HLA-DR/DQ 双转基因小鼠疾病结果的机制。第一个目标是通过分析 HLA-DQ8 分子如何增加 DQ8/DR3 双转基因小鼠的疾病发生率和严重程度：i) HLA 多态性和肽-MHC 亲和力/亲和力在促炎性 IL17 产生中的作用DQ8 限制性 CD4 T 细胞； ii) IL17 导致 DR3DQ8 小鼠脑炎性增加的机制； iii) DQ8 限制性 CD4 T 细胞产生的 GM-CSF 在 DR3DQ8 双转基因小鼠中 EAE 恶化中的作用。在第二个目标中，我们将研究 HLA-DQ6 限制性免疫反应如何导致产生高 IFN3 的调节性 CD4+ T 细胞的产生，特别是 MHC 肽亲和力/功能亲和力的作用。接下来我们将分析 DQ6 限制性 CD4+ T 细胞抑制 HLA-DR3/DQ6 双转基因小鼠中 EAE 的机制。我们还将产生表达疾病易感性 HLA-DR3、疾病保护性 -DQ6 和疾病增强 -DQ8 基因的三重转基因小鼠，以模拟人类杂合条件。该提案中概述的综合研究应该能够深入了解 HLA II 类分子塑造 T 细胞库并调节促炎和抗炎细胞因子谱的机制。这将促进治疗多发性硬化症等炎症性疾病的新型疗法的转化研究开发。公共健康相关性：尽管 HLA 单倍型与多发性硬化症的易感性和发病有关，但过去很难明确 HLA 分子在多发性硬化症中的作用。我们已经使用 HLA 转基因小鼠成功地了解了它们在中枢神经系统炎症和脱髓鞘疾病（例如多发性硬化症）中的作用，并使用实验模型实验性自身免疫性脑脊髓炎（EAE）。这些 EAE 人源化 II 类模型可用于评估未来适用于 MS 患者的潜在治疗方案和肽疫苗。