title: Induced regulatory T cells in allograft tolerance via transient mixed chimerism.
abstract: Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8+T cell responses in tolerant (TOL) recipients, while marked CD4+T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4+cells were FOXP3+in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4+FOXP3+cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism.
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hotta
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Aoyama
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Oura
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tonsho
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kyu Ha
authors.initials: KH
authors.lastname: Huh
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kento
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Biostatistics, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schoenfeld
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Allan
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rex-Neal
authors.initials: RN
authors.lastname: Smith
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Colvin
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: A Benedict
authors.initials: AB
authors.lastname: Cosimi
authors.affiliation: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai