Eosinophilic Myocarditis

嗜酸粒细胞性心肌炎

• 批准号: 8272123
• 负责人: Noel R. Rose
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272123
• 关键词: Acute; Address; Animal Model; Autoimmune Process; Autoimmune Responses; Autoimmunity; Basophils; CD4 Positive T Lymphocytes; Cells; Chemosensitization; Critical Pathways; Cytoplasmic Granules; Decision Making; Dendritic Cells; Development; Disease; Effectiveness; Eicosanoids; Eosinophilia; Figs - dietary; Heart; Heart Diseases; Heart failure; Hematoxylin and Eosin Staining Method; Human; IL4 gene; IL4R gene; IL5 gene; Immune; Immune response; Immunization; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin 4 Receptor; Interleukin-13; Interleukin-17; Lead; Life; Lipids; Mediating; Mediator of activation protein; Modeling; Mouse Strains; Mus; Mutation; Myocarditis; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Point Mutation; Production; Role; STAT6 gene; Severities; Severity of illness; Signal Pathway; Staining method; Stains; Syndrome; T-Lymphocyte; Therapeutic Effect; Time; Transgenic Mice; adaptive immunity; base; cell type; eosinophil; eosinophil peroxidase; improved; in vivo; inhibitor/antagonist; novel; outcome forecast; prevent; programs; research study; response; trafficking; Acute; Address; Animal Model; Autoimmune Process; Autoimmune Responses; Autoimmunity; Basophils; CD4 Positive T Lymphocytes; Cells; Chemosensitization; Critical Pathways; Cytoplasmic Granules; Decision Making; Dendritic Cells; Development; Disease; Effectiveness; Eicosanoids; Eosinophilia; Figs - dietary; Heart; Heart Diseases; Heart failure; Hematoxylin and Eosin Staining Method; Human; IL4 gene; IL4R gene; IL5 gene; Immune; Immune response; Immunization; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin 4 Receptor; Interleukin-13; Interleukin-17; Lead; Life; Lipids; Mediating; Mediator of activation protein; Modeling; Mouse Strains; Mus; Mutation; Myocarditis; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Point Mutation; Production; Role; STAT6 gene; Severities; Severity of illness; Signal Pathway; Staining method; Stains; Syndrome; T-Lymphocyte; Therapeutic Effect; Time; Transgenic Mice; adaptive immunity; base; cell type; eosinophil; eosinophil peroxidase; improved; in vivo; inhibitor/antagonist; novel; outcome forecast; prevent; programs; research study; response; trafficking

DESCRIPTION (provided by applicant): Eosinophilic myocarditis is a rare form of myocarditis with a poorly understood pathogenesis and an exceptionally poor prognosis. Patients with eosinophilic myocarditis present with a rapid, acute onset, and commonly progress to heart failure. We have developed several models of eosinophilic experimental autoimmune myocarditis (Eo-EAM) using either IL5CD2 transgenic mice or mice deficient in both IFN? and IL17A (IFN?-/-IL17A-/-) and immunizing them with myocarditogenic peptide in CFA. Both strains of mice develop severe myocarditis with more than 30% of their heart infiltrate comprised by eosinophils. Based on these observations, we propose the overarching hypothesis that Th2-driven inflammation, especially eosinophilic infiltration, contributes significantly to the most severe forms of immune-mediated heart disease. We propose to investigate the mechanisms underlying the pathogenesis of eosinophilic myocarditis by identifying the most critical cells and mediators that could be targets for a potential treatment. First, in Aim 1, we will examine the induction of eosinophilic autoimmune responses at the level of innate immunity. We hypothesize that early production of IL4 and IL13 by cells activated during the innate immune response leads to autoaggressive Th2 differentiation in the pathogenesis of eosinophilic EAM. We will employ transfer experiments to determine the ability of dendritic cells (Subaim 1.1), basophils (Subaim 1.2), and nuocytes (Subaim 1.3) to induce Eo-EAM. Additionally, we will use in vivo depletions to establish the necessity of these cells in the potentiation of Eo-EAM. In Aim 2, we will study determinants of eosinophil trafficking to the heart and the effectiveness of blocking such pathways to prevent eosinophilic myocarditis. Using IL5-/- mice, we have established that the recruitment of eosinophils to the heart during myocarditis is IL5-independent. In this Aim, we will investigate whether the CCR3 (Subaim 2.1) or eicosanoid lipid derivative pathways (Subaim 2.2) contribute to trafficking of eosinophils to the heart. In Aim 3, T cell decision-making in the pathogenesis of eosinophilic myocarditis will be examined. First, we will determine if IFN¿ and IL17A control development of eosinophilic myocarditis through Th2 responses (Subaim 3.1). To farther examine the sufficiency and necessity of Th2 differentiation for Eo-EAM development, we will employ IL4R¿F709 mice, which carry a point mutation in the IL4 receptor essentially rendering the signaling pathway hyperactive (Subaim 3.2). In Aim 4, we will explore possible therapeutic effects of blockade of one of the major products that eosinophils release upon activation, eosinophil peroxidase (EPO). Dissecting the mechanisms by which different cell types and cell mediators drive eosinophilic myocarditis development can lead to greater understanding of the pathogenesis of eosinophilic myocarditis and suggest ways in which this life-threatening disease can be prevented or treated. PUBLIC HEALTH RELEVANCE: Eosinophilic myocarditis is a rare form of myocarditis with a poorly understood pathogenesis and an exceptionally poor prognosis. By analyzing the critical pathways responsible for this disease we will seek opportunities to improve treatment of this and other eosinophilic inflammatory disorders.

描述（由适用提供）：嗜酸性心肌炎是一种罕见的心肌炎形式，其发病机理知之甚少，预后异常差。嗜酸性心肌炎患者患有快速，急性发作，通常会发展为心力衰竭。我们使用IL5CD2转基因小鼠或两种IFN中缺乏的小鼠开发了几种嗜酸性实验性自身免疫性心肌炎（EO-EAM）模型？和IL17A（IFN？ - / - IL17A - / - ），并用CFA中的心肌型肽对其进行免疫。两种小鼠的菌株都患有严重的心肌炎，其中30％的心脏浸润包括嗜酸性粒细胞。基于这些观察结果，我们提出了一个总体假设，即Th2驱动的感染，尤其是嗜酸性粒细胞浸润，对免疫介导的心脏病的最严重形式产生了显着贡献。我们建议通过鉴定可能是潜在治疗的靶标的最关键的细胞和介体来研究嗜酸性心肌炎发病机理的基础机制。首先，在AIM 1中，我们将研究先天免疫史的嗜酸性自身免疫反应的诱导。我们假设在先天免疫增强期间激活的细胞早期生产IL4和IL13会导致嗜酸性EAM发病机理中自动侵略性Th2分化。我们将采用转移实验来确定树突状细胞（Subaim 1.1），嗜碱性粒细胞（Subaim 1.2）和Nuocytes（Subaim 1.3）诱导EO-EAM的能力。此外，我们将使用体内耗竭来建立这些细胞在EO-EAM潜力中的必要物质。在AIM 2中，我们将研究嗜酸性粒细胞运输的决定者，以及阻止此类途径以预防嗜酸性心肌炎的有效性。使用IL5 - / - 小鼠，我们已经确定在心肌炎期间嗜酸性粒细胞募集到心脏是IL5无关的。在这个目标中，我们将 研究CCR3（Subaim 2.1）或类花生酸脂质衍生途径（Subaim 2.2）是否有助于将嗜酸性粒细胞贩运到心脏。在AIM 3中，T细胞决策在 将检查嗜酸性心肌炎的发病机理。首先，我们将通过TH2反应来确定IFN¿和IL17A是否控制嗜酸性心肌炎的发展（Subaim 3.1）。为了进一步研究EO-EAM发育的TH2分化的充分性和必要的分化，我们将采用IL4R¿F709小鼠，在IL4受体中带有点突变，基本上使信号通路过度活跃（Subaim 3.2）。在AIM 4中，我们将探讨嗜酸性粒细胞嗜酸性嗜酸性过氧化物酶（EPO）释放的主要产物之一的封锁可能的治疗作用。解剖不同细胞类型和细胞介质驱动嗜酸性心肌炎发育的机制可以使人们对嗜酸性粒细胞性心肌炎的发病机理有更多的了解，并提出可以预防或治疗这种威胁生命的疾病的方法。 公共卫生相关性：嗜酸性心肌炎是一种罕见的心肌炎形式，其发病机理知之甚少，预后异常差。通过分析导致该疾病的关键途径，我们将寻求机会改善对这种和其他嗜酸性炎性疾病的治疗。