Role of Natural Killer Cells in Myocarditis and Dilated Cardiomyopathy

描述(申请人提供)：心肌炎，即心脏肌肉的炎症，是40岁以下与心脏相关的死亡的主要原因之一。临床上，超过三分之一的心肌炎病例不可逆转地发展为扩张型心肌病(DCM)，需要心脏移植。在实验性自身免疫性心肌炎(EAM)过程中自然杀伤(NK)细胞的耗竭显著增加了疾病的严重程度，提供了NK细胞可以预防炎症的证据。这一增加伴随着Th2和Th17T细胞亚群的扩张。此外，心脏中嗜酸性粒细胞的增加也被观察到。这表明NK细胞可以直接与适应性免疫系统的成员和粒细胞相互作用。本研究旨在阐明NKs在体内和体外通过在不同的疾病时点耗尽NK细胞以及在极化条件下与NAVE T细胞共培养来调节T细胞反应的机制。这一建议还旨在通过确定NK细胞在调节嗜酸性粒细胞趋化中的作用来了解NK细胞和嗜酸性粒细胞之间的关系。总之，这项研究将为心肌炎的新的和急需的生物治疗提供强有力的背景。 公共卫生相关性：心肌炎和扩张型心肌病(DCM)是年轻人心力衰竭和心源性猝死的主要原因，除完全心脏移植外，DCM没有根治方法。为了开发更好的治疗和预防措施，对心肌炎和DCM背后的免疫机制的研究是非常必要的。我们专注于自然杀伤(NK)细胞，因为研究表明，它们在许多自身免疫性疾病中发挥着重要的保护作用。

DESCRIPTION (provided by applicant): Myocarditis, the inflammation of the heart muscle, is a one of the leading causes of cardiac-related deaths in individuals under the age of 40. Clinically, more than a third of myocarditis cases proceed irreversibly into dilated cardiomyopathy (DCM) which requires cardiac transplantation. Depletion of natural killer (NK) cells during of experimental autoimmune myocarditis (EAM) significantly increases levels of disease severity, providing evidence that NK cells can protect against inflammation. This increase was accompanied by expansions in Th2 and Th17 T cell subsets. Additionally, increases of eosinophils in the heart were also observed. This suggests that NK cells can directly interact with both members of the adaptive immune system and granulocytes. This proposal seeks to elucidate the mechanisms by which NKs modulate T cell responses in vivo and in vitro by depleting NK cells during different disease timepoints and by co-culturing NK cells with na¿ve T cells under polarizing conditions. This proposal also aims to understand the relationship between NK cells and eosinophils by determine the role of NK cells in regulating eosinophil chemotaxis. All together, this research will provide a strong background for a novel and much needed biological therapy for myocarditis. PUBLIC HEALTH RELEVANCE: Myocarditis and dilated cardiomyopathy (DCM) are major causes of heart failure and sudden cardiac death for young adults with no curative treatments for DCM other than a complete heart transplant. Research into the immune mechanisms behind myocarditis and DCM is greatly needed in order to develop better therapies and preventative measures. We focus on natural killer (NK) cells because studies indicate they serve an important protective role in a number of autoimmune diseases.