Pathogenesis of Experimental Autoimmune Myocarditis

当心脏不能提供足够的含氧血液供应时，就会发生心力衰竭。 周围组织的代谢需求。失败的主要原因有很多， 实际上所有这些都可能伴随着心肌炎症，作为一种“适应性”过程， 其实弊大于利对心脏抗原，特别是心肌肌球蛋白的自身免疫， 人类和实验动物在经历了广泛的炎症性心脏病后， 感染、缺血性损伤和心脏毒性药物治疗。一个强大的实验模型 自身免疫性心肌炎（EAM）是由易感菌株的免疫引起的 用完全弗氏佐剂中的纯化肌球蛋白对小鼠进行免疫。在过去十年中， 以表征EAM模型，并且已知其（i）至少最初由CD4+ T细胞介导，和（ii） 双相的，具有促炎阶段，随后是修复和纤维化阶段。我们最近的工作 着重探讨EAM发病的基本机制， 通过恢复外周免疫耐受和血管紧张素治疗自身免疫性心肌炎 转化酶抑制我们组建了一个病理学方面的研究小组， 遗传学，免疫学，分子和细胞生物学的EAM，并建议继续我们的工作， 以下具体目的：（i）阐明炎症的分子发病机制和解决 肌球蛋白诱导的EAM的阶段，重点是这些过程的功能免疫学，（ii） 研究EAM中免疫反应的抗原特异性和外周血的潜力 耐受诱导治疗正在进行的疾病和（iii）探讨的作用， 血管紧张素系统在EAM发病机制中的作用。

Cardiac failure occurs when the heart is unable to deliver a sufficient supply of oxygenated blood to serve the metabolic needs of the peripheral tissues. There are a large number of primary causes of failure, virtually all of which may be accompanied by myocardial inflammation as an "adaptive" process that may actually do more harm than good. Autoimmunity to cardiac antigens, cardiac myosin in particular, may develop during inflammatory heart disease in humans and experimental animals after a wide range of infections, ischemic damage and cardiotoxic drug treatment. A powerful model of experimental autoimmune myocarditis (EAM) has been developed that is initiated by immunization of susceptible strains of mice with purified myosin in complete Freund's adjuvant. Much has been done during the past decade to characterize the EAM model and it is known to be (i) mediated, at least initially, by CD4+ T cells and (ii) biphasic, with a proinflammatory phase followed by a phase of repair and fibrosis. Our recent work has focused on the basic mechanisms of EAM pathogenesis with an emphasis on the prevention and treatment of autoimmune myocarditis by restoration of peripheral immune tolerance and byangiotensin converting enzyme inhibition. We have assembled a research team with expertise in the pathology, genetics, immunology, and molecular and cellular biology of EAM, and propose to continue our work with the following Specific Aims: (i) to elucidate the molecular pathogenesis of the inflammatory and resolution phases of myosin-induced EAM, with a focus on the functional immunology of these processes, (ii)to investigate the antigen specificities of the immune responses in EAM and the potential of peripheral tolerance induction for the treatment of ongoing disease and (iii)to explore the role of the renin angiotensin system in EAM pathogenesis.