Targeting monocyte allorecognition to achieve allograft acceptance

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Abstract: Over the past decades great progress has been made in solid organ transplantation in improving 1-year allograft survival rates, but long-term allograft survival has not improved significantly. Despite the use of maintenance immunosuppression, chronic rejection is one of the main drivers of graft failure in addition to the side effects of maintenance immunosuppressive therapy. Long-term allograft acceptance without the need for maintenance immunosuppression is therefore an unmet clinical need. We have recently discovered that monocyte allorecognition depends on the key step of sensing polymorphic donor SIRPa by CD47 on recipient monocytes. This leads to formation of donor-specific monocyte memory and differentiation of monocytes to mono-DC, which drive rejection and graft pathology. CD47ko mice display monocyte unresponsiveness and less graft pathology, while a donor SIRPa mismatch in human renal allograft recipients is associated with increased 1-year graft fibrosis and shorter 7-year graft survival. In this grant application we hypothesize that long-term allograft acceptance can be achieved by combining T cell costimulation blockade with inhibition of monocyte allorecognition via CD47. The goals of this proposal are a) to develop a translatable model of blocking CD47 in addition to T cell costimulatory blockade to induce long term graft acceptance (Aim 1), and b) to investigate the mechanisms of monocyte unresponsiveness in the absence of CD47 signaling to uncover novel targetable pathways (Aim 2). These studies are significant as they address the unmet clinical need of long-term allograft acceptance without excessive side effects of conventional immunosuppression and are using a novel, specific approach to suppress the innate immune system in addition to the adaptive immune system. Insights gained from these studies are likely to have direct human relevance and could potentially be tested in the clinic.