C-reactive protein orchestrates acute allograft rejection in vascularized composite allotransplantation via subset-selective monocyte activation.

ABSTRACT

INTRODUCTION: Despite recent substantial progress in vascularized composite allotransplantation (VCA), such as face transplantations, short- and long-term allograft survival is severely limited by allograft rejection. The acute-phase response, directly after allogeneic transplantation, represents an immune-inflammatory reaction to ischemia/reperfusion and acts as an early initiator of graft rejection. Acute-phase reactants mediate this immune response via crosstalk with the mononuclear phagocyte system. OBJECTIVE: C-reactive protein (CRP), a well-known marker of inflammation, has pro-inflammatory properties and aggravates ischemia/reperfusion injury. Thus, we investigated how CRP impacts acute allograft rejection. METHODS: Based on clinical observations in facial VCAs, we applied a complex hindlimb transplantation model in rats to investigate whether CRP directly affects transplant rejection. We further analyzed subset-specific infiltration and tissue distribution of recipient-derived monocytes in the early phase of acute rejection and assessed their differential regulation by CRP using intravital imaging. RESULTS: We demonstrate that CRP accelerates allograft rejection and reduces allograft survival via selectively activating non-classical monocytes. The therapeutic stabilization of CRP abrogates this activating effect on monocytes, consequently attenuating acute allograft rejection. Intravital imaging of graft-infiltrating, recipient-derived monocytes during the early phase of acute rejection confirmed their differential regulation by CRP and their crucial role in driving the early stage of graft rejection. CONCLUSION: Differential activation of recipient-derived monocytes by CRP aggravates innate immune response and accelerates clinical allograft rejection Thus, therapeutic targeting of CRP represents a novel promising strategy for preventing acute allograft rejection and potentially reducing chronic allograft rejection.