title: Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation.
abstract: Transplantation of allogeneic organs and tissues represents a lifesaving procedure for a variety of patients affected with end-stage diseases. Although current immunosuppressive therapy prevents early acute rejection, it is associated with nephrotoxicity and increased risks for infection and neoplasia. This stresses the need for selective immune-based therapies relying on manipulation of lymphocyte recognition of donor antigens. The passenger leukocyte theory states that allograft rejection is initiated by recipient T cells recognizing donor major histocompatibility complex (MHC) molecules displayed on graft leukocytes migrating to the host's lymphoid organs. We revisited this concept in mice transplanted with allogeneic skin, heart, or islet grafts using imaging flow cytometry. We observed no donor cells in the lymph nodes and spleen of skin-grafted mice, but we found high numbers of recipient cells displaying allogeneic MHC molecules (cross-dressed) acquired from donor microvesicles (exosomes). After heart or islet transplantation, we observed few donor leukocytes (100 per million) but large numbers of recipient cells cross-dressed with donor MHC (>90,000 per million). Last, we showed that purified allogeneic exosomes induced proinflammatory alloimmune responses by T cells in vitro and in vivo. Collectively, these results suggest that recipient antigen-presenting cells cross-dressed with donor MHC rather than passenger leukocytes trigger T cell responses after allotransplantation.
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Marino
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Babiker-Mohamed
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Crosby-Bertorini
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Paster
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: LeGuern
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Germana
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Uehara
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: James I
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Markmann
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Georges
authors.initials: G
authors.lastname: Tocco
authors.affiliation: Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou