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，其发病机制尚不清楚，预后异常差。嗜酸性心肌炎患者表现为快速、急性发作，通常进展为心力衰竭。我们开发了几种嗜酸性实验性自身免疫性心肌炎（Eo-EAM）模型，使用IL5CD2转基因小鼠或IFN？和IL17A (IFN？-/- il17a -/-)，用致心肌肽免疫。两种小鼠均发生严重的心肌炎，其心脏浸润的30%以上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th2驱动的炎症，特别是嗜酸性粒细胞浸润，在最严重的免疫介导的心脏病形式中起着重要作用。我们建议通过鉴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Aim 1中，我们将在先天免疫水平上研究嗜酸性自身免疫反应的诱导。我们假设在先天免疫反应中激活的细胞早期产生IL4和IL13导致嗜酸性EAM的自身侵袭性Th2分化。我们将采用转移实验来确定树突状细胞（Subaim 1.1）、嗜碱性细胞（Subaim 1.2）和营养细胞（Subaim 1.3）诱导Eo-EAM的能力。此外，我们将使用体内消耗来确定这些细胞在增强Eo-EAM中的必要性。在Aim 2中，我们将研究嗜酸性粒细胞向心脏转运的决定因素，以及阻断这种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向心脏的募集是IL5独立的。在这个目标中，我们将

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.