Pathogenesis of Experimental Autoimmune Myocarditis

实验性自身免疫性心肌炎的发病机制

• 批准号: 7339181
• 负责人: David M. Engman
• 金额: $ 1.9万
• 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/7339181
• 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

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.

当心脏无法提供足够的含氧血液来服务时，就会发生心力衰竭 周围组织的代谢需要。造成故障的主要原因有很多， 事实上，所有这些都可能伴随着心肌炎症，这是一种“适应性”过程，可能会导致心肌炎症。 实际上弊大于利。对心脏抗原（特别是心肌肌球蛋白）的自身免疫可能 在人类和实验动物的炎症性心脏病期间发生广泛的 感染、缺血性损伤和心脏毒性药物治疗。强大的实验模型 自身免疫性心肌炎（EAM）是通过对敏感菌株进行免疫而引发的 在弗氏完全佐剂中纯化肌球蛋白的小鼠。过去十年我们做了很多工作 来表征 EAM 模型，已知它是 (i) 至少在最初由 CD4+ T 细胞介导的，并且 (ii) 双相，先是促炎阶段，然后是修复和纤维化阶段。我们最近的工作有 重点研究EAM发病机制的基本机制，重点是预防和治疗 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。我们组建了一支具有病理学专业知识的研究团队， EAM 的遗传学、免疫学以及分子和细胞生物学，并建议继续与 具体目标如下： (i) 阐明炎症的分子发病机制并解决 肌球蛋白诱导的 EAM 阶段，重点关注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以及外周血的潜力 诱导耐受以治疗持续性疾病并 (iii) 探索肾素的作用 血管紧张素系统在 EAM 发病机制中的作用。