Genetic or Pharmaceutical Blockade of Phosphoinositide 3-Kinase p110δ Prevents Chronic Rejection of Heart Allografts

Abstract

Chronic rejection is the major cause of long-term heart allograft failure. A prominent feature of chronic graft rejection is tissue infiltration by recipient T cells with indirect allospecificity. Phosphoinositol-3-kinase p110δ is a key mediator of T cell receptor signalling, regulating both T cell activation and, importantly, migration of primed T cells to non-lymphoid antigen-rich tissue. The objective of this study was to investigate the effect of genetic or pharmacologic inactivation of PI3K p110δ on the development of chronic allograft rejection in a murine model of minor histocompatibility antigens-mismatched heart allografts. HY-mismatched hearts were transplanted into recipient mice with either genetic or pharmacological targeting of PI3K p110δ signalling. We show that suppression of p110d activity significantly attenuates the development of chronic rejection of heart grafts in the absence of any additional immunosuppressive treatment, while not inducing specific T cell tolerance. PI3K p110d pharmacologic inactivation is effective when initiated after transplantation. We further show that PI3K p110d inhibition acts by impairing the localization of antigen-specific T cells to the heart grafts. We propose that targeting of PI3K p110δ activity is a viable strategy for the treatment of heart allograft chronic rejection in humans.