Eosinophilic Myocarditis

描述（由申请人提供）：嗜酸性心肌炎是一种罕见的心肌炎，其发病机制知之甚少，预后极差。嗜酸细胞性心肌炎患者起病迅速，急性发作，通常进展为心力衰竭。我们已经开发了几种模型嗜酸性粒细胞实验性自身免疫性心肌炎（Eo-EAM）使用IL 5CD 2转基因小鼠或小鼠缺乏IFN？和IL 17 A（IFN？-/- IL 17 A-/-）并用CFA中的心肌发生肽免疫它们。两种品系的小鼠都发生严重的心肌炎，其中超过30%的心脏浸润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，即Th 2驱动的炎症，特别是嗜酸性粒细胞浸润，对最严重的免疫介导的心脏病有显著影响。我们建议通过确定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心肌炎发病机制。首先，在目标1中，我们将在先天免疫水平上检查嗜酸性粒细胞自身免疫应答的诱导。我们推测，IL 4和IL 13的早期生产的先天免疫反应过程中激活的细胞导致自身攻击性Th 2分化的嗜酸性EAM的发病机制。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，我们将使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运输到心脏的决定因素和阻断这种途径预防嗜酸性心肌炎的有效性。使用IL 5-/-小鼠，我们已经确定，在心肌炎的心脏嗜酸性粒细胞的招聘是IL 5-独立的。在这个目标中，我们将 研究CCR 3（Subaim 2.1）或类花生酸脂质衍生物途径（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细胞的决策， 嗜酸性心肌炎的发病机制将被检查。首先，我们将确定IFN？和IL 17 A是否通过Th 2应答控制嗜酸性心肌炎的发展（Subaim 3.1）。为了进一步检查Th 2分化对于Eo-EAM发展的充分性和必要性，我们将使用IL 4 R？F709小鼠，其在IL 4受体中携带点突变，基本上使信号传导途径过度活跃（Subaim 3.2）。在目标4中，我们将探讨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。剖析不同类型的细胞和细胞介质驱动嗜酸性心肌炎发展的机制，可以更好地了解嗜酸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。

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.