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：
8423316
负责人：
HOWARD Lee LIPTON
金额：
$ 33.67万
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/8423316
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.

描述（由申请人提供）：Theiler鼠脑脊髓炎病毒（TMEV）诱导的小鼠脱髓鞘疾病为多发性硬化症提供了高度相关的实验动物模型，因为感染是在其天然宿主中进行的，该宿主为数月慢性，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，并且是富含巨噬细胞的免疫病理学。TMEV诱导的脱髓鞘主要是通过病毒特异性免疫反应介导的，导致促炎性Th1细胞因子IFN？和TNF以及髓鞘蛋白表位T细胞反应。T和B细胞对髓磷脂蛋白表位的应答的报道导致了这样的观点，即当观察到这些自身免疫应答时，在感染后60天后，自身免疫放大了这种病毒诱导的免疫病理学。此外，最近甚至有人认为TMEV引起通过表位扩散触发的慢性T细胞介导的自身免疫性脱髓鞘疾病，而在慢性脱髓鞘中病毒持续存在没有明显作用。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由病毒感染引发的自身免疫性疾病的普遍信念。我们假设这些慢性“自身免疫反应”依赖于持续的病毒感染，并且在没有病毒的情况下不能自我维持。慢性TMEV诱导的脱髓鞘在没有病毒持续存在的情况下是否是自身免疫性的测试是显示抗病毒治疗的持续病毒学应答，但证明对免疫显性髓鞘蛋白表位的连续T细胞应答（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，如果是病毒驱动的，T细胞对髓鞘表位的反应应该减少（表位扩散的损失），T调节细胞应该增加，脱髓鞘应该解决或减缓，并且运动功能应该在没有病毒或病毒负荷较低的情况下恢复。本申请中的这些和其他方法试图通过使用现有技术的实验方法来获得对Theiler鼠脑脊髓炎病毒感染、病毒持续存在和脱髓鞘的宿主和病毒动力学的更完整的理解。