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Title: Study and therapeutic interference of T cell function in pressure overload-induced heart failure
Author: Martini, Elisa
ISNI:       0000 0004 6496 9726
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2017
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Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. We attempted to identify and exploit better targets in cardiac inflammation so as to enable an immunotherapy of HF. We linked T cells with HF development in the gold-standard mouse model of HF and in human HF patients. We inhibited T cell function in vivo via T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept (CTLA-Ig). Administration of abatacept led to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurred via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Treatment also induced production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice were refractive to treatment, whilst protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade could be therapeutically exploited as a possible HF treatment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral