Duality@50: Making progress and looking forward

Myocardial infarction results in necrosis of the heart tissue due to reduced oxygenation, which often leads to maladaptive left ventricular remodeling and heart failure. Despite results in mice suggesting a role for the immune system in the healing or progression to heart failure after myocardial infarction (MI), its role in humans remains largely unknown.

This research proposal aims to investigate the role of immune cells in the pathogenesis of heart failure following MI. We hypothesize that the massive release of mediators of inflammation and self-proteins derived from disrupted cardiomyocytes following the ischemic event may activate both innate and adaptive immune cells, such as CD4+ regulatory T (Treg) cells, CD4+ T helper (Th) cells, and CD8+ T cytotoxic cells that may elicit self-reactivity. Using an in-depth immune profiling approach, we aim to comprehensively characterize all the innate and adaptive immune cell populations present in the peripheral blood of patients at different time points after MI. Furthermore, we aim to verify whether T cells isolated from MI patients exhibit self-reactivity against syngeneic heart functional cells, namely cardiomyocytes. The latter hypothesis will be tested by leveraging an established method to obtain human cardiomyocytes in vitro, using the Induced Pluripotent Stem Cells (iPS) technology. Finally, the T cell receptor (TCR) repertoire of cardiac-reactive T cells will be measured by TCR Vß sequencing and T cell clones will be isolated to verify cardiac-specificity and identify their cognate antigens.

The innovative spirit of this project proposal is rooted in the combination of theoretical and technical expertise from different research domains, including human immunology, iPS technology, and cardiovascular research. This synergistic approach has significant potential to bring a paradigm shift in the emerging field of cardio-immunology.

The in-depth longitudinal analysis of MI patients will allow the identification of novel prognostic biomarkers that are urgently needed for the early identification of MI patients at risk of developing heart failure, and that are useful to orient the therapy accordingly. Furthermore, the screening of T cell reactivity to syngenic iPS-cardiomyocytes will allow to test if immune tolerance to self is compromised upon ischemic necrosis following MI. Finally, the characterization of cardiac-reactive T cells will allow to define their TCR aß sequences and cognate epitopes, which could drive the design of new strategies to monitor the human T cell response to cardiac autoantigens.