Role of Natural Killer Cells in Myocarditis and Dilated Cardiomyopathy

自然杀伤细胞在心肌炎和扩张型心肌病中的作用

• 批准号: 8400774
• 负责人: SuFey Ong
• 金额: $ 4.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2015-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8400774
• 关键词: Activated Natural Killer Cell; Affect; Age; Animals; Antigen-Presenting Cells; Autoimmune Diseases; Autoimmune Process; Biological Response Modifier Therapy; CD4 Positive T Lymphocytes; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell Lineage; Cells; Cessation of life; Chemotaxis; Coculture Techniques; Data; Depressed mood; Development; Dilated Cardiomyopathy; Disease; Environment; Eotaxin; Etiology; Fibroblasts; Fibrosis; Heart; Heart Transplantation; Heart failure; Helper-Inducer T-Lymphocyte; Immune; Immune system; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Interleukin-17; Interleukin-5; Laboratories; Life; Measures; Messenger RNA; Modeling; Mus; Myocarditis; Myocardium; Natural Killer Cells; Pathology; Patients; Peptides; Population; Process; Production; Reporting; Research; Role; Severity of illness; Staging; Sudden Death; T cell response; T-Cell Activation; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Transgenic Mice; cytokine; effective therapy; eosinophil; granulocyte; high risk; human CCL26 protein; in vivo; member; migration; novel; sudden cardiac death; trafficking; young adult

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.

描述（由申请人提供）：心肌炎，心肌炎症，是40岁以下个体心脏相关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地发展为扩张型心肌病（DCM），需要心脏移植。实验性自身免疫性心肌炎（EAM）期间自然杀伤（NK）细胞的耗竭显著增加了疾病的严重程度，这为NK细胞可以预防炎症提供了证据。这种增加伴随着Th2和Th17 T细胞亚群的扩增。此外，还观察到心脏中嗜酸性粒细胞增加。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。该提案旨在阐明NK通过在不同疾病时间点消耗NK细胞以及在极化条件下将NK细胞与幼稚T细胞共培养来调节体内和体外T细胞应答的机制。本研究的目的还在于通过确定NK细胞在调节嗜酸性粒细胞趋化性中的作用来了解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型和急需的生物治疗提供强有力的背景。 公共卫生关系：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，除了完整的心脏移植外，没有治愈DCM的治疗方法。为了开发更好的治疗和预防措施，非常需要研究心肌炎和DCM背后的免疫机制。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起着重要的保护作用。