Role of Natural Killer Cells in Myocarditis and Dilated Cardiomyopathy

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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.