Pathogenesis of Experimental Autoimmune Myocarditis

实验性自身免疫性心肌炎的发病机制

• 批准号: 7424971
• 负责人: David M. Engman
• 金额: $ 38.55万
• 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/7424971
• 关键词: Affect; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies; Antigens; Area; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Blood; CD4 Positive T Lymphocytes; Captopril; Cardiac; Cardiac Myosins; Cells; Delayed Hypersensitivity; Development; Disease; Enzyme Inhibition; Enzyme-Linked Immunosorbent Assay; Epitopes; Experimental Models; Failure; Fibrosis; Flow Cytometry; Freund' s Adjuvant; Genetic; Heart; Heart Diseases; Heart failure; Histopathology; Human; Humoral Immunities; Immune; Immune Tolerance; Immune response; Immunization; Immunohistochemistry; Immunology; Immunotherapy; Infection; Inflammation; Inflammatory; Measurement; Mediating; Metabolic; Methods; Modeling; Molecular; Molecular and Cellular Biology; Mouse Strains; Myocardial; Myocarditis; Myosin ATPase; Numbers; Organ; Pathogenesis; Pathology; Pathway interactions; Peptidyl-Dipeptidase A; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Play; Population; Prevention; Process; Production; Range; Renin-Angiotensin System; Research; Resolution; Role; Specificity; T-Cell Proliferation; Tissues; Work; chemokine; cytokine; in vivo; inhibitor/antagonist; prevent; repaired; restoration

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（由申请人提供）：心脏衰竭发生在心脏无法提供足够的含氧血液来满足周围组织的代谢需求时。失败的主要原因有很多，几乎所有这些原因可能伴随着心肌炎症，这是一个“自适应”过程，实际上可能弊大于利。心脏抗原的自身免疫性尤其是心脏肌球蛋白，在广泛感染，缺血性损伤和心脏毒性药物治疗后，可能在人类和实验动物的炎症性心脏病期间发展。已经开发了一种强大的实验性自身免疫性心肌炎（EAM）模型，该模型是通过在完整弗洛伦德的辅助剂中纯化的带有纯化肌球蛋白的小鼠的易感菌株引发的。在过去的十年中，已经做了很多事情来表征EAM模型，并且众所周知，它至少在最初是由CD4+ T细胞和（ii）Biphasic介导的，具有促炎相，然后是修复和纤维化阶段。我们最近的工作集中在EAM发病机理的基本机制上，重点是通过恢复外周免疫耐受性和血管紧张素转化酶抑制来预防和治疗自身免疫性心肌炎。我们已经组建了一个在EAM的病理，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，并建议以以下特定目的继续进行我们的工作：（i）阐明肌动蛋白诱导的EAM的炎症和分辨率阶段的分子发病机理，并针对这些过程（II）的特定性，即II的特定过程（II），II，II的特定效应，即II，II，II的影响力，即II，II综合效应的效果。 EAM和外周耐受性诱导对正在进行的疾病的治疗和（iii）探索肾素血管紧张素系统在EAM发病机理中的作用。