Viral suppression of CNS autoimmunity

中枢神经系统自身免疫的病毒抑制

• 批准号: 8241904
• 负责人: Stephen A. Stohlman
• 金额: $ 34.34万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241904
• 关键词: Acute; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Area; Attention; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Blood - brain barrier anatomy; Bone Marrow; CNS autoimmunity; Cells; Central Nervous System Viral Diseases; Clinical; Data; Data Analyses; Demyelinations; Diphtheria Toxin; Encephalomyelitis; Environment; Environmental Risk Factor; Epitopes; Event; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Genetic; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunohistochemistry; Individual; Infection; Infectious Agent; Inflammation; Informal Social Control; Interferon Type II; Interferons; Interleukin-17; Interleukin-9; Kinetics; Mediating; Modeling; Multiple Sclerosis; Murine hepatitis virus; Mus; Myelin; Neuraxis; Organ; Pathology; Plasma Cells; Precipitation; Reagent; Regulation; Regulatory T-Lymphocyte; Relapse; Residual state; Resolution; Rodent Model; Sterility; Symptoms; T-Lymphocyte; Testing; Time; Tissues; Transgenic Mice; Viral; Viral Antigens; Virus; Virus Diseases; autoreactive T cell; base; chronic demyelination; cytokine; diphtheria toxin receptor; environmental agent; human data; neutralizing antibody; novel; novel strategies; prevent; promoter; public health relevance; tool; viral RNA; virus-induced demyelination

DESCRIPTION (provided by applicant): Autoimmunity is an attack on the host carried out by its own immune system. Genetic and environmental agents, i.e., infectious agents, are thought to be major contributing factors in both the induction of autoimmunity and in precipitation of relapse events. Significant attention has been given to possible mechanisms of autoimmune activation following infection. However, little is understood concerning the mechanisms that prevent autoimmunity, especially following an infection that produces pathology similar or identical to an autoimmune disease. In this proposal we will use a viral infection of the central nervous system (CNS) that induces significant demyelination, a hallmark of human multiple sclerosis (MS) and murine experimental autoimmune encephalitis (EAE), without progressing to autoimmunity. The virus used is the glial tropic JHM strain of mouse hepatitis virus (JHMV). This infection of the murine CNS produces a nonfatal encephalomyelitis. The host's immune system clears infectious virus from the CNS but is unable to affect sterile immunity, resulting in a persistence viral infection confined to the CNS. Demyelination is a hallmark finding associated with both the acute infection and, importantly, the persistent infection. Following viral induced demyelination autoreactive T cells are not present during the window of maximal demyelination, but only during viral persistence, after resolution of the infection and re-established blood brain barrier integrity. Nevertheless there is no evidence of an autoimmune response associated with these self reactive T cells. This proposal examines the mechanisms regulating both the induction and suppression of autoreactive T cells. Our overall hypothesis is that extensive viral induced demyelination following acute infection induces a milieu within the CNS which suppresses the effector function of self reactive T cells. This proposal defines the kinetics of activation and CNS retention of self reactive T cells secreting interferon gamma (IFN-?) interleukin (IL)-17, and IL-9 and defines the requirement for demyelination in the activation of self reactive T cells. The concept that suppression of self reactivity is a residual effect of acute viral encephalomyelitis is tested by adoptive transfer of encephalitogenic Th1, Th9 and Th17 cells into persistently infected mice. Finally a novel transgenic mouse which allows depletion of regulatory T cells within the CNS during viral persistence will prove that regulatory T cells prevent expression of self reactive T cell effector function. Using both virus specific reagents and tools developed to understand EAE regulation these data will provide a mechanistic understanding of the regulation self reactive T cells induced by a viral infection. In addition, the data will provide the first demonstration of a viral induced mechanism suppressing effector function specifically within the target tissue, preventing autoimmune attack by self reactive T cells. PUBLIC HEALTH RELEVANCE: Genetic and environmental factors both contribute to the induction of autoimmunity and in precipitation of relapse events. Viruses are one of the environmental agents implicated in a number of autoimmune diseases, including multiple sclerosis. Possible mechanisms of autoimmune activation following infection have been proposed based on both human data and analysis of rodent models. However, the presence of potentially autoimmune inducing T cells in normal individuals suggests a control mechanism. This proposal examines the mechanisms regulating both induction and suppression of autoreactive T cells following a viral infection of the central nervous system. It tests the hypothesis that potentially autoimmune inducing T cells are activated during a viral infection due to destruction of the same cells that are the targets of autoimmunity. However, as part of the inflammation which controls virus, a suppressive anti- inflammatory environment is established in the central nervous system which prevents autoimmunity.

描述(申请人提供)：自身免疫是一种由自身免疫系统对宿主进行的攻击。遗传和环境因素，即感染性因素，被认为是诱发自身免疫和复发事件的主要促成因素。感染后自身免疫激活的可能机制引起了人们的极大关注。然而，对于阻止自身免疫的机制，特别是在感染后产生类似或相同于自身免疫性疾病的病理之后，人们了解很少。在这项提案中，我们将使用中枢神经系统(CNS)的病毒感染，导致显著的脱髓鞘，这是人类多发性硬化症(MS)和小鼠实验性自身免疫性脑炎(EAE)的特征，而不会进展为自身免疫。使用的病毒是小鼠肝炎病毒(JHMV)的嗜胶质JHM株。这种对小鼠中枢神经系统的感染会产生一种非致命性的脑脊髓炎。宿主的免疫系统清除了中枢神经系统中的传染性病毒，但无法影响无菌免疫，导致病毒感染持续局限于中枢神经系统。脱髓鞘是急性感染的标志性表现，更重要的是持续感染。病毒诱导脱髓鞘后，自身反应性T细胞在最大脱髓鞘窗口期不存在，而仅在病毒持续期间、感染消退并重建血脑屏障完整性后出现。然而，没有证据表明与这些自身反应性T细胞相关的自身免疫反应。这项建议研究了自体反应性T细胞的诱导和抑制的调节机制。我们的总体假设是，急性感染后广泛的病毒诱导的脱髓鞘导致中枢神经系统内的环境，从而抑制自身反应性T细胞的效应功能。这一建议定义了分泌干扰素-γ的自身反应性T细胞的激活和中枢神经系统滞留的动力学。白介素17和白介素9，并定义了自身反应性T细胞激活中脱髓鞘的要求。通过将致脑源性Th1、Th9和Th17细胞过继转移到持续感染的小鼠体内，检验了自我反应性抑制是急性病毒性脑脊髓炎的后遗症的概念。最后，一种新的转基因小鼠可以在病毒持续期间耗尽中枢神经系统内的调节性T细胞，这将证明调节性T细胞阻止自我反应性T细胞效应器功能的表达。使用病毒特异性试剂和为了解EAE调节而开发的工具，这些数据将提供对病毒感染诱导的自我反应性T细胞调节的机制理解。此外，这些数据将首次证明病毒诱导的机制抑制靶组织内特定的效应器功能，防止自身反应性T细胞的自身免疫攻击。 与公共卫生相关：遗传和环境因素都有助于诱导自身免疫和避免复发事件的发生。病毒是与包括多发性硬化症在内的许多自身免疫性疾病有关的环境因素之一。基于人类数据和对啮齿动物模型的分析，提出了感染后自身免疫激活的可能机制。然而，在正常人中潜在的自身免疫诱导T细胞的存在表明了一种控制机制。这项建议研究了中枢神经系统病毒感染后诱导和抑制自身反应性T细胞的调节机制。它测试了一种假设，即潜在的自身免疫诱导T细胞在病毒感染期间被激活，因为作为自身免疫目标的相同细胞被破坏。然而，作为控制病毒的炎症的一部分，中枢神经系统中建立了一个抑制性抗炎环境，阻止了自身免疫。