权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Does chronic Theiler's demyelination require viral persistence?

慢性泰勒脱髓鞘症是否需要病毒持续存在？

基本信息

批准号：
8321170
负责人：
HOWARD Lee LIPTON
金额：
$ 34.85万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321170
关键词：
Alleles Antibodies Antigens Antiviral Agents Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Belief Blood - brain barrier anatomy Brain CD11 Antigens CD4 Positive T Lymphocytes CD8B1 gene Capsid Cells Cerebrospinal Fluid Cessation of life Chronic Clinical Demyelinating Diseases Demyelinations Dendritic Cells Diphtheria Toxin Dot Immunoblotting Epitopes Experimental Animal Model Experimental Autoimmune Encephalomyelitis Frequencies Genetic Genomics Growth Herpesvirus Type 3 Human IL2RA gene ITGAM gene Immune Immune response Immunologics Infection Infiltration Inflammatory Interferons Intramuscular Intravenous Kinetics Label Lead Lesion Liposomes Major Histocompatibility Complex Measles Mediating Messenger RNA Modeling Mononuclear Motor Mouse Strains Multiple Sclerosis Mus Myelin Myelin Basic Proteins Myelin Proteins Neuraxis Oligodendroglia Orthophosphate Pathogenesis Phase Phosphate Buffer Physiologic pulse Production Proteins Proteolipids RNA RNA Viruses Reaction Regulatory T-Lymphocyte Relative (related person)Reporting Ribavirin Rodent Model Role Rubella Saline Serum Subacute Sclerosing Panencephalitis T cell response T-Lymphocyte TMEV Testing Transgenic Organisms Viral Viral Load result Virus Virus Diseases bean chronic demyelination cytokine diphtheria toxin receptor immunopathology in vivo intraperitoneal laser capture microdissection lymph nodes macrophage monocyte neurovirulence peripheral blood proteolipid protein 139-151 research study response viral RNA virus-induced demyelination

项目摘要

DESCRIPTION (provided by applicant): Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice provides a highly relevant experimental animal model for multiple sclerosis because infection is in its natural host that is chronic for many months, influenced by major histocompatibility complex genetic alleles, includes both CD4+ and CD8+ T-cells in macrophage-rich lesions, and is a macrophage-rich immunopathology. TMEV-induced demyelination is primarily immune-mediated via virus-specific immune responses that lead to production of proinflammatory Th1 cytokines IFN? and TNF¿ as well as myelin protein epitope T cell responses. Reports of both T and B cell responses to myelin protein epitopes have led to the notion that autoimmunity amplifies this virus-induced immunopathology after day 60 pi when these autoimmune responses are observed. Moreover, it has recently even been argued that TMEV causes a chronic T cell-mediated autoimmune demyelinating disease triggered via epitope spreading with no apparent role for viral persistence in chronic demyelination. The possibility that autoimmunity evolves in a viral model of multiple sclerosis is appealing because it supports the widespread belief that multiple sclerosis is an autoimmune disease triggered by a virus infection. We hypothesize that these chronic "autoimmune responses" depend on persistent viral infection and are not self-sustaining in the absence of virus. A test of whether chronic TMEV-induced demyelination is autoimmune in the absence of viral persistence is to show a sustained virological response with antiviral treatment yet demonstrate continuous T cell responses to immunodominant myelin protein epitopes (epitope spreading), decreased T regulatory cells, progression of demyelination and loss of motor function. However, if virus- driven, T cell responses to myelin epitope should decrease (loss of epitope spreading), T regulatory cells should increase, demyelination should resolve or be slowed, and motor function should be restored with the absence of or with a lower viral burden. These and other approaches in this application seeks to gain a more complete understanding of host and viral dynamics of Theiler's murine encephalomyelitis virus infection, viral persistence and demyelination by using state-of-the art experimental approaches. PUBLIC HEALTH RELEVANCE: Theiler's murine encephalomyelitis virus-induced demyelinating disease in mice provides a highly relevant experimental animal model for multiple sclerosis because infection is in its natural host, chronic for many months, influenced by major histocompatibility complex genetic alleles, contains both CD4+ and CD8+ T-cells in macrophage-rich lesions, and is a virus-induced immunopathology. Analysis of this viral model promises to provide a better understanding of the pathogenesis of MS, and perturbations such as macrophage depletion and antiviral treatment should elucidate the extent of the role of autoimmunity in demyelination.

描述（由申请人提供）：Theiler's小鼠脑脊髓炎病毒（TMEV）诱导的小鼠脱髓鞘病为多发性硬化症提供了一个高度相关的实验动物模型，因为感染发生在其自然宿主体内，慢性数月，受主要组织相容性复合体遗传等位基因的影响，在富含巨噬细胞的病变中包括CD4+和CD8+ t细胞，是一种富含巨噬细胞的免疫病理。tmev诱导的脱髓鞘主要是免疫介导的，通过病毒特异性免疫反应导致促炎Th1细胞因子IFN的产生。和TNF¿以及髓磷脂蛋白表位T细胞的反应。关于T细胞和B细胞对髓鞘蛋白表位的反应的报道导致了这样一种观点，即当观察到这些自身免疫反应时，自身免疫在60天后放大了这种病毒诱导的免疫病理。此外，最近甚至有人认为，TMEV引起慢性T细胞介导的自身免疫性脱髓鞘疾病，通过表位扩散触发，而在慢性脱髓鞘中没有明显的病毒持续作用。自身免疫在多发性硬化症病毒模型中进化的可能性很有吸引力，因为它支持了多发性硬化症是一种由病毒感染引发的自身免疫性疾病的普遍观点。我们假设这些慢性“自身免疫反应”依赖于持续的病毒感染，在没有病毒的情况下不是自我维持的。在没有病毒持续存在的情况下，一项关于慢性tmev诱导的脱髓鞘是否为自身免疫性的测试显示，抗病毒治疗具有持续的病毒学反应，但显示出对免疫优势髓磷脂蛋白表位的持续T细胞反应（表位扩散），T调节细胞减少，脱髓鞘进展和运动功能丧失。然而，如果病毒驱动，T细胞对髓磷脂表位的反应应该减少（表位扩散丧失），T调节细胞应该增加，脱髓鞘应该消退或减缓，运动功能应该在没有或较低的病毒负荷下恢复。本应用程序中的这些方法和其他方法旨在通过使用最先进的实验方法，更全面地了解Theiler小鼠脑脊髓炎病毒感染、病毒持久性和脱髓鞘的宿主和病毒动力学。