Pathogenesis of Autoimmune Myocarditis

我们的长期目标是了解慢性心肌炎的发病机制， 超过50%的患者在5年内死亡或需要心脏移植。我们将使用一个 实验性自身免疫性心肌炎（EAM）的小鼠模型，其中疾病是在易感的 用心肌肌球蛋白或其心肌生成肽在佐剂中免疫小鼠。根据我们的调查结果 IFN-γ敲除（KO）小鼠和IL-13敲除小鼠发生严重心肌炎，我们假设IFN-γ 和IL-13是心肌炎中有益的细胞因子。我们选择关注这两个调解人， 可能导致心肌炎和其他炎症性心血管疾病的新疗法。具体 该建议的目的是：SA 1：确定IFN-γ对细胞凋亡途径的影响， 自身反应性淋巴细胞。由于IFN-γ KO小鼠具有比IFN-γ KO小鼠更少的凋亡CD 4 + T淋巴细胞， 在野生型对照中，我们假设IFN-γ限制了自身反应性T细胞的存活，从而保护了T细胞。 严重的心肌炎我们将测试操纵IFN-γ依赖性途径的效果， 细胞凋亡在体外和体内对心肌炎严重程度的影响。SA 2：研究IL-13在 EAM的发展。我们的初步结果表明，IL-13也有保护作用的EAM。IL-13 与IL-4以及STAT 6依赖性信号通路共享共同受体，但它具有 在EAM中的相反效果。我们将研究IL-13的发病机制，通过（i）在不同时间阻断细胞因子， 在疾病期间;（ii）确定心肌炎期间IL-13的细胞来源和动力学;（iii）测试心肌炎期间IL-13的细胞来源和动力学。 假设IL-13利用新的受体或新的信号通路。SA 3：评估 重组（r）IFN-γ和/或rIL-13在不同心肌炎模型中的治疗效果。在人类中 多种抗原和表位被鉴定为自身免疫应答的靶标。所以我们会 检查重组细胞因子治疗在不同心肌炎模型中的效率：（i） （ii）全肌球蛋白诱导的EAM;（iii）病毒诱导的心肌炎;和 (iv)肌钙蛋白L诱导的EAM。与公共卫生的相关性：非常需要改进治疗方法 可以减缓，停止，甚至逆转心脏的炎症变化。我们建议扩大 了解心肌炎的发病机制，以便合理化新的生物治疗方法。

Our long-term goal is to understand pathogenesis of chronic myocarditis, a disease that has a grim prognosis with more than 50% of patients dying or needing a heart transplant within 5 years. We will use a murine model of experimental autoimmune myocarditis (EAM), where the disease is induced in susceptible mice by immunization with cardiac myosin or its myocarditogenic peptide in adjuvant. Based on our findings that IFN-y knockout (KO) mice and IL-13 KO mice develop severe myocarditis, we hypothesize that IFN-y and IL-13 are beneficial cytokines in myocarditis. We chose to focus on these two mediators because they may lead to novel therapies for myocarditis and other inflammatory cardiovascular diseases. The specific aims of this proposal are: SA1: To determine the influence of IFN-y upon apoptotic pathways in autoreactive lymphocytes in EAM . Since IFN-y KO mice have fewer apoptotic CD4+ T lymphocytes than wild type controls, we hypothesize that IFN-y limits the survival of autoreactive T cells, thus protecting the heart from severe myocarditis. We will test the effect of manipulation of IFN-y dependent pathways of apoptosis in vitro and in vivo on the severity of myocarditis. SA2: To study the role of IL-13 in the progression of EAM. Our preliminary results show that IL-13 also has a protective role in EAM. IL-13 shares a common receptor with IL-4 as well as the STAT6 dependent signaling pathway, yet it has an opposite effect in EAM. We will study the pathogenesis of IL-13 by (i) blocking the cytokine at different times during the disease; (ii) determining cellular origin and kinetics of IL-13 during myocarditis; (iii) testing the hypothesis that IL-13 utilizes a new receptor or a newsignaling pathway. SA3: To evaluate the therapeutic effects of recombinant (r) IFN-y and/or rIL-13 in different myocarditis models. In humans multiple antigens and epitope were identified as targets of autoimmune responses. Therefore, we will examine the efficiency of the recombinant cytokine treatment in different myocarditis models: (i) myocarditogenic peptide induced EAM; (ii) whole myosin induced EAM; (iii) virus-induced myocarditis; and (iv) troponin l-induced EAM. Relevance to Public Health: There is a great need for improved therapies that could slow down, stop, or even reverse inflammatory changes in the heart. We propose to broaden our knowledge of the pathogenesis of myocarditis, in order to rationalize new biologic approaches to treatment.