Eosinophilic Myocarditis

嗜酸粒细胞性心肌炎

• 批准号: 8646995
• 负责人: Noel R. Rose
• 金额: $ 40.18万
• 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/8646995
• 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

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.

描述（由申请人提供）：嗜酸粒细胞性心肌炎是一种罕见的心肌炎，其发病机制尚不清楚，且预后极差。嗜酸性粒细胞性心肌炎患者起病迅速、急性，通常进展为心力衰竭。我们使用 IL5CD2 转基因小鼠或缺乏 IFN? 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 中的心肌生成肽对其进行免疫。两种品系的小鼠都会出现严重的心肌炎，其心脏浸润物中有超过 30% 由嗜酸性粒细胞组成。基于这些观察结果，我们提出了一个总体假设：Th2 驱动的炎症，尤其是嗜酸性粒细胞浸润，对最严重形式的免疫介导的心脏病有显着影响。我们建议通过识别可能成为潜在治疗靶点的最关键细胞和介质来研究嗜酸性粒细胞性心肌炎发病机制的潜在机制。首先，在目标 1 中，我们将在先天免疫水平上检查嗜酸性自身免疫反应的诱导。我们假设先天免疫反应过程中激活的细胞早期产生 IL4 和 IL13 导致嗜酸性 EAM 发病机制中的自身攻击性 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) 和核细胞 (Subaim 1.3) 诱导 Eo-EAM 的能力。此外，我们将利用体内耗竭来确定这些细胞在 Eo-EAM 增强中的必要性。在目标 2 中，我们将研究嗜酸性粒细胞转运至心脏的决定因素以及阻断此类途径以预防嗜酸性粒细胞性心肌炎的有效性。使用IL5-/-小鼠，我们已经确定心肌炎期间嗜酸性粒细胞向心脏的募集是不依赖于IL5的。为了这个目标，我们将 研究 CCR3 (Subaim 2.1) 或类二十烷酸脂质衍生物途径 (Subaim 2.2) 是否有助于嗜酸性粒细胞向心脏的运输。在目标 3 中，T 细胞决策 将检查嗜酸粒细胞性心肌炎的发病机制。首先，我们将确定 IFN 和 IL17A 是否通过 Th2 反应控制嗜酸性粒细胞性心肌炎的发展（Subaim 3.1）。为了进一步检查 Th2 分化对于 Eo-EAM 发育的充分性和必要性，我们将使用 IL4R¿F709 小鼠，该小鼠在 IL4 受体中携带点突变，本质上导致信号通路过度活跃 (Subaim 3.2)。在目标 4 中，我们将探索阻断嗜酸性粒细胞激活后释放的主要产物之一——嗜酸性粒细胞过氧化物酶 (EPO) 的可能治疗效果。剖析不同细胞类型和细胞介质驱动嗜酸性粒细胞性心肌炎发展的机制可以使人们更好地了解嗜酸性粒细胞性心肌炎的发病机制，并提出预防或治疗这种危及生命的疾病的方法。