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

Abstract

IntroductionDespite advancements in transplant immunology and vascularized composite allotransplantation (VCA), the longevity of allografts remains hindered by the challenge of allograft rejection. The acute-phase response, an immune-inflammatory reaction to ischemia/reperfusion that occurs directly after allogeneic transplantation, serves as a catalyst for graft rejection. This immune response is orchestrated by acute-phase reactants through intricate crosstalk with the mononuclear phagocyte system. ObjectiveC-reactive protein (CRP), a well-known marker of inflammation, possesses pro-inflammatory properties and exacerbates ischemia/reperfusion injury. Thus, we investigated how CRP impacts acute allograft rejection. MethodsPrompted by clinical observations in facial VCAs, we employed a complex hindlimb transplantation model in rats to investigate the direct impact of CRP on transplant rejection. ResultsOur findings demonstrate that CRP expedites allograft rejection and diminishes allograft survival by selectively activating non-classical monocytes. Therapeutic stabilization of CRP abrogates this activating effect on monocytes, thereby attenuating acute allograft rejection. Intravital imagining of graft-infiltrating, recipient-derived monocytes during the early phase of acute rejection corroborated their differential regulation by CRP and their pivotal role in driving the initial stages of graft rejection. ConclusionThe differential activation of recipient-derived monocytes by CRP exacerbates the innate immune response and accelerates clinical allograft rejection. Thus, therapeutic targeting of CRP represents a novel and promising strategy for preventing acute allograft rejection and potentially mitigating chronic allograft rejection.