Innate Immunity in Myocarditis

心肌炎的先天免疫

基本信息

  • 批准号:
    7658608
  • 负责人:
  • 金额:
    $ 18.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-04-01 至 2011-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the myocardium which often follows microbial infections. Enteroviruses (picornaviruses) and adenoviruses are most frequently implicated in clinical disease. We have developed a murine model of coxsackievirus B3 (CVB3) myocarditis. Pathogenicity requires virus induction of a strong antigen-specific CD4+Th1 (IFN+) cell response while conditions which promote a CD4+Th2 (IL-4+) response prevent myocarditis. T cells expressing the V4 T cell receptor are crucial to generation of CD4+Th1 immunity. It is well accepted that innate effectors such as + cells modulate adaptive immune responses. The accepted mechanisms for this modulation depend upon cytokine release by the innate effectors which provides an environmental milieu favorable to a specific Th response; and innate effector impact on antigen presenting cells resulting in changes in accessory molecule or cytokine expression by the antigen presenting cells leading to alterations in CD4+ cell responses. To the best of our knowledge, we are the only laboratory hypothesizing that + cells directly bind to CD4+ cells modulating the Th phenotype. We have shown that + cells selectively kill CD4+Th2 cells leaving the CD4+Th1 cells intact. Currently, nearly all studies show that CD4+Th1 cells are selectively susceptible to Fas-dependent apoptosis while CD4+Th2 cells are remarkably resistant. Our data is diametrically opposite of accepted knowledge. The major question is why in our CVB3 model, CD4+Th2 cells are apoptosis susceptible and how much the selective elimination of Th2 cells by + cells contributes to the CD4+Th1 dominance in CVB3 infected mice. We hypothesize that there would be differences in CD1d, Fas or anti-apoptotic factors, such as c-FLIPL, between CD4+ Th1 and Th2 cells and that these differences allow the selective killing of the Th2 cells. Elimination of effector CD4+ cells at the end of antigenic stimulation conserves resources and space in the hemopoietic compartment, but immune contraction should apply to both CD4+Th1 and Th2 cells. Contraction of only CD4+Th1 cells could allow progressive accumulation of CD4+Th2 and ultimate imbalance of the immune system. Innate effectors such as + cells may play an important role in eliminating activated CD4+Th2 cells. The question central to this proposal is how innate effectors distinguish between Th1 and Th2 cells, killing the latter but not the former. The Specific Aims are: 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo; (2) Determine if CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells; (3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis.; and (4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and elevated levels in Th1 cells protects them from V4+ cell mediated killing. . PUBLIC HEALTH RELEVANCE: This grant will investigate the role of Vgamma4+ T cells in selectively killing activated CD4+Th2 cells by Fas-dependent mechanisms, as a method for immune contraction after an immune response. The Specific Aims are to 1) Determine if + cells are only required for activating CD4+ cells or for maintaining the activated cells in vivo. 2) Determine if Fas or CD1d expression on CD4+ cells is required for + cell immunomodulation of the CD4+ response in vivo and the role of IFN production by V4+ cells. 3) Determine whether CD1d or Fas expression on CD4+ Th1 or Th2 cell clones differs and explains the increased susceptibility of Th2 clones to V4+ cell induced apoptosis. 4) Determine if c-FLIPL expression differs between CD4+Th1 and Th2 cells and whether elevated levels in Th1 cells protects them from V4+ cell mediated killing.
描述(由申请人提供):心肌炎是心肌的炎症,通常是在微生物感染之后进行的。肠病毒(PICORNAVIRASE)和腺病毒最常见于临床疾病。我们已经开发了一种Coxsackievivirus B3(CVB3)心肌炎的鼠模型。致病性需要病毒诱导强抗原特异性CD4+TH1(IFN+)细胞反应,同时促进CD4+TH2(IL-4+)反应的条件预防心肌炎。表达V4 T细胞受体的T细胞对CD4+Th1免疫的产生至关重要。众所周知的是, +细胞等先天效应子可以调节适应性免疫反应。该调节的公认机制取决于先天效应子的细胞因子释放,该效应提供了有利于特定TH反应的环境环境;和先天效应子对抗原呈现细胞的影响,导致抗原呈现细胞的辅助分子或细胞因子表达的变化,从而导致CD4+细胞反应的改变。据我们所知,我们是唯一一个假设 +细胞直接结合CD4 +细胞调节TH表型的实验室。我们已经表明,+细胞选择性地杀死CD4+Th1细胞完整的CD4+TH2细胞。目前,几乎所有研究都表明,CD4+Th1细胞有选择地易受FAS依赖性凋亡,而CD4+Th2细胞具有明显的抗性。我们的数据与公认的知识完全相反。主要问题是为什么在我们的CVB3模型中,CD4+TH2细胞是凋亡的易感性,以及+细胞对Th2细胞的选择性消除的程度有助于CVB3感染小鼠的CD4+Th1优势。我们假设CD1D,FAS或抗凋亡因子(例如C-FLIPL)在CD4+ Th1和Th2细胞之间存在差异,并且这些差异允许选择性杀死Th2细胞。在抗原刺激结束时消除效应的CD4+细胞可以保存闻型室中的资源和空间,但免疫收缩应适用于CD4+ TH1和TH2细胞。仅CD4+Th1细胞的收缩可以允许CD4+TH2的逐渐积累和免疫系统的最终失衡。先天效应子(例如 +细胞)可能在消除活化的CD4 + Th2细胞中起重要作用。该提案的核心问题是,先天效应者如何区分Th1和Th2细胞,杀死后者,但没有杀死前者。具体目的是:1)确定 +细胞是仅仅仅激活CD4 +细胞或在体内维持活化的细胞; (2)确定CD4+细胞上的CD1D表达是否需要体内CD4+反应的+细胞免疫调节以及V4+细胞产生IFN的作用; (3)确定在CD4+ TH1或Th2细胞克隆上的CD1D或FAS表达是否有所不同,并解释了Th2克隆对V4+细胞诱导凋亡的敏感性增加。 (4)确定C-FLIPL表达在CD4+ TH1和Th2细胞之间是否有所不同,而Th1细胞中的水平升高可以保护它们免受V4+细胞介导的杀伤的侵害。 。公共卫生相关性:该赠款将研究VGAMMA4+ T细胞通过FAS依赖性机制选择性杀死活化的CD4+ TH2细胞的作用,这是免疫反应后免疫收缩的一种方法。具体目的是1)确定 +细胞是仅需激活CD4 +细胞还是维持活体活化细胞的必需。 2)确定CD4+细胞上的FAS或CD1D表达是否需要体内CD4+反应的+细胞免疫调节以及V4+细胞产生IFN的作用。 3)确定在CD4+ TH1或Th2细胞克隆上的CD1D或FAS表达是否有所不同,并解释了Th2克隆对V4+细胞诱导凋亡的敏感性增加。 4)确定C-FLIPL表达在CD4+ TH1和Th2细胞之间是否有所不同,以及Th1细胞中升高的水平是否保护它们免受V4+细胞介导的杀伤的侵害。

项目成果

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Sally A Huber其他文献

Sally A Huber的其他文献

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{{ truncateString('Sally A Huber', 18)}}的其他基金

Tregulatory cells in myocarditis
心肌炎中的调节细胞
  • 批准号:
    8645714
  • 财政年份:
    2011
  • 资助金额:
    $ 18.81万
  • 项目类别:
Tregulatory cells in myocarditis
心肌炎中的调节细胞
  • 批准号:
    8266284
  • 财政年份:
    2011
  • 资助金额:
    $ 18.81万
  • 项目类别:
Tregulatory cells in myocarditis
心肌炎中的调节细胞
  • 批准号:
    8452724
  • 财政年份:
    2011
  • 资助金额:
    $ 18.81万
  • 项目类别:
Tregulatory cells in myocarditis
心肌炎中的调节细胞
  • 批准号:
    8119246
  • 财政年份:
    2011
  • 资助金额:
    $ 18.81万
  • 项目类别:
Innate Immunity in Myocarditis
心肌炎的先天免疫
  • 批准号:
    7780450
  • 财政年份:
    2009
  • 资助金额:
    $ 18.81万
  • 项目类别:
T reg Cells in Myocarditis
心肌炎中的 T reg 细胞
  • 批准号:
    7341114
  • 财政年份:
    2007
  • 资助金额:
    $ 18.81万
  • 项目类别:
T reg Cells in Myocarditis
心肌炎中的 T reg 细胞
  • 批准号:
    7760619
  • 财政年份:
    2007
  • 资助金额:
    $ 18.81万
  • 项目类别:
T reg Cells in Myocarditis
心肌炎中的 T reg 细胞
  • 批准号:
    7173106
  • 财政年份:
    2007
  • 资助金额:
    $ 18.81万
  • 项目类别:
T reg Cells in Myocarditis
心肌炎中的 T reg 细胞
  • 批准号:
    7564131
  • 财政年份:
    2007
  • 资助金额:
    $ 18.81万
  • 项目类别:
Sex in Myocarditis
心肌炎中的性行为
  • 批准号:
    6911795
  • 财政年份:
    2005
  • 资助金额:
    $ 18.81万
  • 项目类别:

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