T reg Cells in Myocarditis

心肌炎中的 T reg 细胞

• 批准号: 7564131
• 负责人: Sally A Huber
• 金额: $ 38万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564131
• 关键词: Adenovirus Infections; Adenoviruses; Adoptive Transfer; Amino Acids; Animals; Antigens; Autoimmunity; Blood; CD4 Positive T Lymphocytes; Capsid Proteins; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Clinical; Coxsackie Viruses; Dendritic Cells; Disease; Endothelial Cells; Enterovirus; Family Picornaviridae; Generations; Glycolipids; Immune; Immunity; Immunosuppression; Immunosuppressive Agents; Infection; Inflammation; Interleukin-10; Lymphocyte; Major Histocompatibility Complex; Mediating; Modeling; Mus; Mutation; Myocarditis; Myocardium; Nature; Pathogenicity; Population; Predisposition; Recombinants; Relative (related person); Reporting; Resistance; Role; Spleen; T-Cell Receptor; T-Lymphocyte; Up-Regulation; Variant; Viral; Virus; Virus Diseases; base; cytokine; experience; in vivo; killer T cell; macrophage; microbial; mutant; protein activation

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. However, both types of virus are extremely common and not everyone experiencing an enterovirus/adenovirus infection will develop myocarditis. Both host and viral factors determine viral pathogenicity. We have developed a murine model of coxsackievirus B3 myocarditis where the H3 variant of the virus induces severe myocarditis while a mutant of the H3 virus, designated H310A1, is non-myocarditic. The H3 and H310A1 variants differ by a single non-conserved amino acid mutation in the VP2 capsid protein. The H310A1 variant stimulates CD4+ T regulatory (T reg) cells which actively suppress the pathogenic immunity induced by H3 virus infection. The T reg cells are CD4+CD25+FoxP3+. A major difference in H3 and H310A1 infections is that H3 virus is a potent inducer of systemic TNFa while H310A1 infection induces little of this cytokine. Studies by others and us have shown that exogenous administration of recombinant TNFa exacerbates myocarditis susceptibility in normally resistant mice. Thus, giving TNFa to H310A1 infected mice restores myocarditis susceptibility and greatly reduces TGF¿ expression by T reg cells. Since TGF¿ mediates immunosuppression at least by TH3 cells, we hypothesize that TNFa modulates TH3 cell activation or function. This is surprising since TNFa has been reported to promote the Tr1 type of T reg cell. It is possible that TNFa may have different effects on induction of distinct types of T reg cells, promoting some and inhibiting others. In the current model, we believe that TNFa might abrogate T reg cells through induction of CD1d, a non-classical MHC class I protein, and activation of T cells expressing the V?4 T cell receptor. V?4+ cells in viral myocarditis are CDId-restricted and adoptive transfer of activated V?4+ cells into H310A1 infected mice restores myocarditis susceptibility. In this proposal, we wish to: 1. Determine whether T reg cells are Tr1, Th3 or natural T reg cells which means they should suppress adaptive immunity through IL-10, TGF¿ or cell-cell contact; 2. Determine the relative roles of infection (TLR), TNFa, CD1d and V?4+ T cells in generation or abrogation of T reg cells; and 3. Determine whether the T reg cells are antigen specific (virus), cardiovascular specific (autoimmunity), or non-antigen specific.

描述（由适用提供）：心肌炎是心肌的感染，通常遵循微生物感染。肠病毒（PICORNAVIRASE）和腺病毒最常在临床疾病中实施。但是，两种类型的病毒都非常普遍，并不是每个患有肠肠病毒/腺病毒感染的人都会患上心肌炎。宿主和病毒因素都决定了病毒致病性。我们已经开发了一种Coxsackievivirus B3心肌炎的鼠模型，其中该病毒的H3变体诱导严重的心肌炎，而指定为H310A1的H3病毒的突变体是非肌心脑的。 H3和H310A1变体在VP2衣壳蛋白中的单个非保守氨基酸突变而有所不同。 H310A1变体刺激CD4+ T调节（T Reg）细胞，该细胞积极抑制H3病毒感染诱导的致病性免疫学。 T Reg单元为CD4+CD25+FOXP3+。 H3和H310A1感染的主要差异是H3病毒是全身性TNFA的潜在诱导剂，而H310A1感染几乎没有诱导这种细胞因子。其他人和美国的研究表明，重组TNFA的外源给药加剧了正常抗性小鼠的心肌炎的敏感性。这使TNFA使H310a1感染的小鼠恢复了心肌炎的敏感性，并大大降低了T Reg细胞的TGF表达。由于TGF至少通过TH3细胞介导免疫抑制，因此我们假设TNFA调节Th3细胞的激活或功能。这是令人惊讶的，因为据报道TNFA促进TR1类型的T reg细胞。 TNFA可能对不同类型的T reg细胞的诱导有不同的影响，从而促进了某些细胞并抑制其他细胞。在当前模型中，我们认为TNFA可能会通过诱导CD1D（一种非经典MHC I类蛋白）消除T reg细胞，并激活表达V？4 T细胞受体的T细胞。 V？4+病毒心肌炎中的细胞是CDID限制性限制和活性V？4+细胞向H310A1感染的小鼠的适应性转移，可恢复心肌炎的敏感性。在此提案中，我们希望：1。确定T Reg细胞是TR1，TH3或天然T型细胞，这意味着它们应通过IL-10，TGF抑制适应性免疫学抑制适应性免疫学或细胞 - 细胞接触； 2。确定感染（TLR），TNFA，CD1D和V？4+ T细胞在T Reg细胞的产生或废除中的相对作用；和3。确定T Reg细胞是抗原特异性（病毒），心血管特异性（自身免疫性）还是非抗原特异性。