Origin And Function Of Host-derived Dendritic Cells In Organ Transplants

Abstract:Historically, people think direct allorecognition pathway by donor dendritic cells (DC) play a dominant role in acute rejection after organ transplantation. However, recent studies show that indirect allorecognition by recipient DC play a more important role in acute allograft rejection. Donor DC exit organ grafts after transplantation and are replaced by host DC. The origin and function of these tissue-resident, host DC however is unknown. Using flow cytometry and2-photon intravital microscopy, we observed rapid replacement of donor DC by host DC in both syngeneic and allogeneic heart and kidney grafts within3days after transplantation, and demonstrated that the vast majority of host DC were monocyte-derived (Mono-DC). By day7, allografts harbored>5-fold more DC than syn grafts and>45-fold more than native tissue. Enhanced DC accumulation in allografts was inhibited by treating recipients with cyclosporine A, indicating a crucial role for the host alloimmune response in DC influx. Mono-DC accumulation was mainly dependent on fractalkine receptor (CX3CR1) expressed on host monocytes. Host DC that infiltrated grafts localized to perivascular areas, extended dendrites into the vessel lumens, mediated the transmigration of cognate effector T cells (Teff) into the graft, and continued to make stable contacts with the Teff after they had transmigrated. Hence, host Mono-DC amass rapidly in transplanted organs, replacing donor DC, and accelerate rejection by enhancing Teff migration, retention, and activation. Our results provide novel insights into the pathogenesis and treatment of allograft rejection.