title: Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells.
abstract: Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg preloaded with cell membrane vesicles from allogeneic peripheral blood mononuclear cells induce T cell hyporesponsiveness to donor alloantigen (alloAg) in vitro. These donor alloAg-pulsed autologous DCreg (1.4-3.6 × 106/kg) were administered intravenously, 1 day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 immunoglobulin [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n = 6 historical controls) and 29 days with control unpulsed DCreg (n = 2), to 56 days with donor Ag-pulsed DCreg (n = 5) was associated with evidence of modulated host CD4+and CD8+T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4 Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days posttransplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen.
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: M B
authors.initials: MB
authors.lastname: Ezzelarab
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: D
authors.initials: D
authors.lastname: Raich-Regue
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A F
authors.initials: AF
authors.lastname: Zahorchak
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A
authors.initials: A
authors.lastname: Perez-Gutierrez
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A
authors.initials: A
authors.lastname: Humar
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: M
authors.initials: M
authors.lastname: Wijkstrom
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: M
authors.initials: M
authors.lastname: Minervini
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI.
authors.forename: R W
authors.initials: RW
authors.lastname: Wiseman
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: D K C
authors.initials: DKC
authors.lastname: Cooper
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A E
authors.initials: AE
authors.lastname: Morelli
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear; D008253:Macaca mulatta; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*; D014019:Tissue Donors; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous
chemical_list: D007519:Isoantigens
keywords: T cell biology; animal models: nonhuman primate; basic (laboratory) research/science; dendritic cell; fusion proteins and monoclonal antibodies: belatacept; immunobiology; immunosuppressant; immunosuppression/immune modulation; kidney transplantation/nephrology; mechanistic target of rapamycin (mTOR); translational research/science