Exploration and MOdulation of CD8 T cells in myocardial InfarctION – EMOTION
Cardiovascular diseases, including stroke and ischemic heart disease, are expected to be the main cause of death worldwide within the next 15 years, despite a better management of risk factors such as hypercholesterolemia and hypertension. A large body of experimental and translational evidence support a major role for innate immunity in adverse heart remodelling following myocardial infarction (MI). More recently, our group and others have shown that B and CD4+ T lymphocytes are also differentially involved in this process. However, little is know about the role of cytotoxic CD8+ T cells.
On the basis of very encouraging pilot data, we hypothesize that CD8+ T cells are rapidly recruited within the ischemic heart acute MI, become activated in an antigen-specific manner, and promote deleterious cardiac remodelling. An acute and transient CD8+ T cell depleting strategy could be a promising therapeutic approach to limit heart tissue damage following acute MI. The hypothesis will be tested using both in vitro and in vivo approaches. In vitro, we will test CD8+ T cell cytoxicity on non-ischemic and ischemic cardiomyocytes. In vivo, we will use two complementary approaches: Selective CD8 depletion in immunocompetent mouse models of acute MI, and reconstitution of Rag2-/- immunodeficient mice with WT CD8+ T cells or CD8+ T deficient for a specific gene of interest, which will allow identification of the main pathogenic CD8+ T cell-dependent mechanisms. In parallel, we will analyze CD8+ T cell infiltration and CD8+ T cell associated cytokines and degranulation products in human tissue samples (myocardial biopsies, circulating T cells and plasma). We will also seek for associations between circulating CD8+ T cells markers (number, activation or plasma degranulation products) and cardiovascular events in patients with acute MI. This project should shed new light on the pathogenesis of cardiovascular diseases and could enable the design of novel immune-modulatory strategies in humans.
Monsieur Ziad MALLAT (Inserm U970)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
APHP Service de pharmacologie, Hopital saint-Antoine
Inserm U970 Inserm U970
Inserm U970 Institut National de la santé et de la recherche médicale
AP-HP Service d'anatomopathologie, H.E.G. Pompidou
Help of the ANR 340,024 euros
Beginning and duration of the scientific project: September 2016 - 36 Months