Investigation of the regulation of the innate immune response by C-reactive protein in vascularized composite allotransplantation (VCA)

• Applicant: Professor Dr. Steffen Ulrich Eisenhardt
• Subject Area: General and Visceral Surgery ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450025008

The field of reconstructive microsurgery has made significant progress by the introduction of vascularized composite tissue allotransplantation (VCA) the most common being hand and face transplantations, which are slowly gaining popularity in reconstructive surgery. However, the wide-spread clinical acceptance is limited by the side effects of long-term immuno-suppression and the risk of transplant vasculopathy leading to chronic transplant rejection. Therefore, in order to further develop this promising field of surgical reconstruction, we must target the clinical problems before expanding these still highly experimental reconstructive strategies. There is growing evidence that cells of the mononuclear phagocyte system (MPS) including monocytes and macrophages as part of the innate immune response, are critical in priming of the immune response in the initial inflammatory stage after transplantation characterized by ischemia/reperfusion injury (IRI) as well as in the long-term allograft survival. Chronic rejection is understood to be dependent on a chronic inflammatory process leading to transplant vasculopathy, in which graft-infiltrating macrophages play a significant role. Vasculopathy is characterized by intimal proliferation and progressive narrowing of the arterial lumen resulting in ischemic changes of the allograft, fibrosis, and dysfunction. Previously we have shown that the homopentameric acute phase reactant C-reactive protein (pCRP) is regulating the innate immune response via a conformational change towards pro-inflammatory pCRP* mediated by activated cell membranes on activated or necrotic cells. pCRP* is mediating a selective activation of the CD14dim/CD16+ monocyte subset that has been identified as a key cell of the MPS in acute allograft rejection. Therefore, we want to test the hypothesis, that conformationally altered CRP (pCRP*) is a key mediator of IRI leading to increased acute allograft rejection via activation of CD14dim/CD16+ monocytes. We will use an animal model of VCA investigate the role of CD14dim/CD16+ in acute allograft rejection. In this model we will track the fate of graft-infiltrating pCRP*-stimulated CD14dim/CD16+ monocytes over time in the allograft. We hypothesize that graft-infiltrating non-classical monocytes will turn into sessile pro-inflammatory primed macrophages that activate the adaptive immune response, fuel intimal proliferation and fibrosis ultimately leading to chronic allograft rejection. This pathway might be linking exacerbated acute postoperative inflammation with an increased rate of chronic transplant failure.

• DFG Programme: Research Grants