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Eosinophilic Myocarditis

嗜酸粒细胞性心肌炎

基本信息

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
项目类别：
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

项目摘要

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(申请人提供)：嗜酸性心肌炎是一种罕见的心肌炎，发病机制不甚清楚，预后极差。嗜酸性心肌炎患者起病迅速、急性，通常进展为心力衰竭。我们利用IL5CD2转基因小鼠或同时缺失两种干扰素的小鼠建立了几种嗜酸性实验性自身免疫性心肌炎(EO-EAM)模型。和IL17A(干扰素？-/-IL17A-/-)，并在CFA中用致心肌钙素免疫。这两个品系的小鼠都会患上严重的心肌炎，其心脏浸润液的30%以上由嗜酸性粒细胞组成。基于这些观察，我们提出了一个最重要的假设，即Th2驱动的炎症，特别是嗜酸性粒细胞的渗透，在最严重的免疫介导的心脏病中起着重要作用。我们建议通过识别最关键的细胞和介质来研究嗜酸性心肌炎的发病机制，这些细胞和介质可能是潜在的治疗靶点。首先，在目标1中，我们将在天然免疫水平上研究嗜酸性自身免疫反应的诱导。我们推测，在嗜酸性EAM的发病机制中，先天免疫反应中激活的细胞早期产生IL-4和IL-13导致自身侵袭性Th2分化。我们将通过转移实验来确定树突状细胞(Subaim 1.1)、嗜碱性粒细胞(Subaim 1.2)和有核细胞(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增强EO-EAM中的必要性。在目标2中，我们将研究嗜酸性粒细胞转运到心脏的决定因素，以及阻断这种途径预防嗜酸性心肌炎的有效性。利用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IL5的。为了实现这一目标，我们将研究CCR3(Subaim 2.1)或二十烷基类脂质衍生途径(Subaim 2.2)是否有助于嗜酸性粒细胞运输到心脏。在目标3中，T细胞决策在本课程将探讨嗜酸性心肌炎的发病机制。首先，我们将确定干扰素和IL17A是否通过Th2反应(Subaim 3.1)控制嗜酸性心肌炎的发展。为了进一步检验Th2分化对EO-EAM发育的充分性和必要性，我们将使用IL4R？F709小鼠，它们携带IL4受体的点突变，实质上使信号通路过度活跃(Subaim 3.2)。在目标4中，我们将探讨阻断嗜酸性粒细胞激活时释放的主要产物之一--嗜酸性粒细胞过氧化物酶(EPO)的可能治疗作用。剖析不同细胞类型和细胞介质推动嗜酸性心肌炎发展的机制，有助于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威胁生命的疾病的方法。