Study and Therapeutic Interference of T Cell Function in Pressure Overload-induced Heart Failure

Martini, Elisa (2017). Study and Therapeutic Interference of T Cell Function in Pressure Overload-induced Heart Failure. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000c6a9

Abstract

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.

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About

  • Item ORO ID
  • 50857
  • Item Type
  • PhD Thesis
  • Keywords
  • heart failure; inflammation of the heart; T cells; cytokines
  • Academic Unit or School
  • Faculty of Science, Technology, Engineering and Mathematics (STEM)
  • Associated Research Centre
  • IRCCS Istituto Clinico Humanitas (ICH)
  • Copyright Holders
  • © 2017 The Author
  • Depositing User
  • Elisa Martini

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