Impact of donor extracellular vesicle release on recipient cell “cross‐dressing” following clinical liver and kidney transplantation

In several murine models of transplantation, the “cross‐dressing” of recipient antigen presenting cells (APCs) with intact donor major histocompatibility complex (MHC) derived from allograft‐released small extracellular vesicles (sEVs) has been recently described as a key mechanism in eliciting and sustaining alloimmune responses. Investigation of these processes in clinical organ transplantation has, however, been hampered by the lack of sensitivity of conventional instruments and assays. We have employed advanced imaging flow cytometry (iFCM) to explore the kinetics of allograft sEV release and the extent to which donor sEVs might induce cross‐dressing following liver and kidney transplantation. We report for the first time that recipient APC cross‐dressing can be transiently detected in the circulation shortly after liver, but not kidney, transplantation in association with the release of HLA‐bearing allograft‐derived sEVs. In liver transplant recipients the majority of circulating cells exhibiting donor HLA are indeed cross‐dressed cells and not passenger leukocytes. In keeping with experimental animal data, the downstream functional consequences of the transfer of circulating sEVs harvested from human transplant recipients varies depending on the type of transplant and time posttransplant. sEVs released shortly after liver, but not kidney, transplantation exhibit immunoinhibitory effects that could influence liver allograft immunogenicity. The release of donor‐derived extracellular vesicles bearing donor HLA at the time of liver but not kidney transplantation is associated with the emergence of circulating, cross‐dressed recipient antigen presenting cells that exhibit an immunosuppressive phenotype. See the editorial on page 2319 and the companion article on page 2372.