Pathogenesis of Experimental Autoimmune Myocarditis

描述（由申请人提供）：当心脏无法输送足够的含氧血液以满足外周组织的代谢需求时，会发生心力衰竭。有大量的失败的主要原因，几乎所有这些都可能伴随着心肌炎症作为一个“适应性”的过程，实际上可能弊大于利。对心脏抗原，特别是心肌肌球蛋白的自身免疫，可在人类和实验动物的炎症性心脏病期间在广泛的感染、缺血性损伤和心脏毒性药物治疗后发展。实验性自身免疫性心肌炎（EAM）的一个强大的模型已经开发出来，这是由免疫敏感品系的小鼠与纯化的肌球蛋白在完全弗氏佐剂。在过去的十年中，已经做了很多工作来表征EAM模型，并且已知它是（i）至少最初由CD4+ T细胞介导的，以及（ii）双相的，具有促炎阶段，随后是修复和纤维化阶段。近年来，我们的工作主要集中在EAM发病的基本机制上，重点是通过恢复外周免疫耐受和抑制血管紧张素转换酶来预防和治疗自身免疫性心肌炎。我们已经组建了一个研究团队，拥有EAM病理学，遗传学，免疫学以及分子和细胞生物学方面的专业知识，并建议继续我们的工作，具体目标如下：（i）阐明肌球蛋白诱导的EAM的炎症和消退阶段的分子发病机制，重点是这些过程的功能免疫学，（ii）研究EAM中免疫应答的抗原特异性和外周耐受诱导用于治疗正在进行的疾病的潜力，以及（iii）探索肾素血管紧张素系统在EAM发病机制中的作用。

DESCRIPTION (provided by applicant): 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 by angiotensin 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.