Pathogenesis of Experimental Autoimmune Myocarditis

实验性自身免疫性心肌炎的发病机制

• 批准号: 7150838
• 负责人: David M. Engman
• 金额: $ 37.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150838
• 关键词: autoantigens; autoimmune disorder; captopril; delayed hypersensitivity; disease /disorder model; epitope mapping; flow cytometry; histopathology; humoral immunity; immune tolerance /unresponsiveness; immunocytochemistry; immunopathology; laboratory mouse; lymphocyte proliferation; molecular pathology; myocarditis; myosins; renin angiotensin system

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.

描述(申请人提供)：当心脏不能提供足够的有氧血液供应以满足外周组织的代谢需要时，就会发生心力衰竭。失败的主要原因有很多，几乎所有的原因都可能伴随着心肌炎症，这是一种“适应性”过程，实际上可能弊大于利。在人类和实验动物的炎症性心脏病期间，在广泛的感染、缺血损伤和心脏毒性药物治疗后，对心脏抗原，特别是心肌肌球蛋白的自身免疫可能会形成。用纯化的肌球蛋白在完全弗氏佐剂中免疫易感小鼠，建立了一种有效的实验性自身免疫性心肌炎(EAM)模型。在过去的十年里，人们已经做了很多工作来描述EAM模型，众所周知，它是(I)至少最初由CD4+T细胞介导的，(Ii)双相的，伴随着促炎阶段之后是修复和纤维化阶段。我们最近的工作集中在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。我们已经组建了一支在EAM的病理学、遗传学、免疫学以及分子和细胞生物学方面具有专业知识的研究团队，并建议继续我们的工作，以实现以下具体目标：(I)阐明肌球蛋白诱导的EAM炎症和溶解阶段的分子发病机制，重点研究这些过程的功能免疫学；(Ii)研究EAM免疫反应的抗原特异性以及诱导外周耐受治疗EAM的可能性；以及(Iii)探讨肾素血管紧张素系统在EAM发病机制中的作用。