Viral suppression of CNS autoimmunity

中枢神经系统自身免疫的病毒抑制

基本信息

  • 批准号:
    8492177
  • 负责人:
  • 金额:
    $ 33.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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,感染因子被认为是诱导自身免疫和沉淀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受到了极大的关注。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的病理学的感染之后。在这个提议中,我们将使用中枢神经系统(CNS)的病毒感染,其诱导显著的脱髓鞘,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)的标志,而不进展为自身免疫。使用的病毒是小鼠肝炎病毒(JHMV)的嗜胶质JHM株。这种鼠中枢神经系统的感染产生非致命性脑脊髓炎。宿主的免疫系统清除CNS中的感染性病毒,但不能影响无菌免疫,导致持续性病毒感染局限于CNS。脱髓鞘是与急性感染相关的标志性发现,重要的是,与持续感染相关。在病毒诱导的脱髓鞘后,自身反应性T细胞在最大脱髓鞘的窗口期间不存在,而仅在病毒持续存在期间,在感染消退和重新建立血脑屏障完整性之后。然而,没有证据表明与这些自身反应性T细胞相关的自身免疫反应。该建议检查调节自身反应性T细胞的诱导和抑制的机制。我们的总体假设是,急性感染后广泛的病毒诱导的脱髓鞘诱导CNS内的环境,抑制自身反应性T细胞的效应功能。该提案定义了分泌干扰素γ(IFN-?)的自身反应性T细胞的激活和CNS保留的动力学。白细胞介素(IL)-17和IL-9,并定义了自身反应性T细胞活化中脱髓鞘的需要。通过将致脑炎性Th 1、Th 9和Th 17细胞过继转移到持续感染的小鼠中来测试自身反应性抑制是急性病毒性脑脊髓炎的残余效应的概念。最后,一种新的转基因小鼠,它允许在病毒持续存在期间耗尽CNS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细胞效应子功能的表达。使用病毒特异性试剂和工具来理解EAE调控,这些数据将提供对病毒感染诱导的自身反应性T细胞调控的机制理解。此外,这些数据将首次证明病毒诱导的机制特异性抑制靶组织内的效应子功能,防止自身反应性T细胞的自身免疫攻击。 公共卫生相关性:遗传和环境因素都有助于诱导自身免疫和复发事件的沉淀。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子之一。基于人类数据和啮齿动物模型的分析,已经提出了感染后自身免疫激活的可能机制。然而,在正常个体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。该提案研究了中枢神经系统病毒感染后自身反应性T细胞的诱导和抑制的调节机制。它测试了这样的假设,即潜在的自身免疫诱导T细胞在病毒感染期间由于破坏作为自身免疫靶的相同细胞而被激活。然而,作为控制病毒的炎症的一部分,在中枢神经系统中建立抑制性抗炎环境,其防止自身免疫。

项目成果

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Stephen A. Stohlman其他文献

Resistance to fatal central nervous system disease by mouse hepatitis virus, strain JHM
  • DOI:
    10.1007/bf01563919
  • 发表时间:
    1978-12-01
  • 期刊:
  • 影响因子:
    2.900
  • 作者:
    Stephen A. Stohlman;Jeffrey A. Frelinger
  • 通讯作者:
    Jeffrey A. Frelinger

Stephen A. Stohlman的其他文献

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{{ truncateString('Stephen A. Stohlman', 18)}}的其他基金

Viral suppression of CNS autoimmunity
中枢神经系统自身免疫的病毒抑制
  • 批准号:
    8241904
  • 财政年份:
    2011
  • 资助金额:
    $ 33.14万
  • 项目类别:
Viral suppression of CNS autoimmunity
中枢神经系统自身免疫的病毒抑制
  • 批准号:
    8105529
  • 财政年份:
    2011
  • 资助金额:
    $ 33.14万
  • 项目类别:
Viral suppression of CNS autoimmunity
中枢神经系统自身免疫的病毒抑制
  • 批准号:
    8703814
  • 财政年份:
    2011
  • 资助金额:
    $ 33.14万
  • 项目类别:
Regulation of Gender Dependent EAE Susceptibility
性别依赖性 EAE 易感性的调节
  • 批准号:
    6833506
  • 财政年份:
    2004
  • 资助金额:
    $ 33.14万
  • 项目类别:
Regulation of Gender Dependent EAE Susceptibility
性别依赖性 EAE 易感性的调节
  • 批准号:
    7384434
  • 财政年份:
    2004
  • 资助金额:
    $ 33.14万
  • 项目类别:
Regulation of Gender Dependent EAE Susceptibility
性别依赖性 EAE 易感性的调节
  • 批准号:
    7037529
  • 财政年份:
    2004
  • 资助金额:
    $ 33.14万
  • 项目类别:
Regulation of Gender Dependent EAE Susceptibility
性别依赖性 EAE 易感性的调节
  • 批准号:
    6726366
  • 财政年份:
    2004
  • 资助金额:
    $ 33.14万
  • 项目类别:
Regulation of Gender Dependent EAE Susceptibility
性别依赖性 EAE 易感性的调节
  • 批准号:
    7251520
  • 财政年份:
    2004
  • 资助金额:
    $ 33.14万
  • 项目类别:
Regulation of Gender Dependent EAE Susceptibility
性别依赖性 EAE 易感性的调节
  • 批准号:
    7198509
  • 财政年份:
    2004
  • 资助金额:
    $ 33.14万
  • 项目类别:
Support Core
支持核心
  • 批准号:
    6657938
  • 财政年份:
    2003
  • 资助金额:
    $ 33.14万
  • 项目类别:

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