Viral suppression of CNS autoimmunity

中枢神经系统自身免疫的病毒抑制

• 批准号: 8105529
• 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/8105529
• 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; 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（由申请人提供）：自身免疫是宿主自身免疫系统对宿主的攻击。遗传和环境因素，即感染因素，被认为是诱导自身免疫和沉淀复发事件的主要因素。对感染后自身免疫激活的可能机制给予了极大的关注。然而，关于预防自身免疫的机制知之甚少，特别是在产生与自身免疫性疾病相似或相同病理的感染后。在这个提议中，我们将使用中枢神经系统（CNS）的病毒感染诱导显著脱髓鞘，人类多发性硬化症（MS）和小鼠实验性自身免疫性脑炎（EAE）的标志，没有发展到自身免疫。使用的病毒是嗜胶质性小鼠肝炎病毒（JHMV）的JHM株。这种小鼠中枢神经系统感染产生非致命性脑脊髓炎。宿主的免疫系统从中枢神经系统清除感染性病毒，但无法影响无菌免疫，导致持续的病毒感染局限于中枢神经系统。脱髓鞘是一个标志性的发现与急性感染，重要的是，持续感染。在病毒诱导脱髓鞘后，自身反应性T细胞不存在于最大脱髓鞘窗口期，而只存在于病毒持续存在期间，在感染消退和重新建立血脑屏障完整性之后。然而，没有证据表明自身免疫反应与这些自身反应性T细胞相关。本研究探讨了调节自身反应性T细胞诱导和抑制的机制。我们的总体假设是，急性感染后广泛的病毒诱导脱髓鞘诱导了中枢神经系统内抑制自身反应性T细胞效应功能的环境。本研究定义了分泌干扰素γ (IFN- γ)、白细胞介素(IL)-17和IL-9的自反应性T细胞的激活和中枢神经系统保留动力学，并定义了自反应性T细胞激活过程中脱髓鞘的需要。通过将致脑性Th1、Th9和Th17细胞过继转移到持续感染的小鼠体内，验证了自我反应性抑制是急性病毒性脑脊髓炎残留效应的概念。最后，一种新型转基因小鼠在病毒持续存在期间允许消耗中枢神经系统内的调节性T细胞，这将证明调节性T细胞阻止自身反应性T细胞效应功能的表达。利用病毒特异性试剂和开发的工具来理解EAE调节，这些数据将提供对病毒感染诱导的调节自身反应性T细胞的机制理解。此外，这些数据将首次证明病毒诱导的机制特异性地抑制靶组织内的效应物功能，防止自身反应性T细胞的自身免疫攻击。