title: Regulatory dendritic cell infusion prolongs kidney allograft survival in nonhuman primates.
abstract: We examined the influence of regulatory dendritic cells (DCreg), generated from cytokine-mobilized donor blood monocytes in vitamin D3 and IL-10, on renal allograft survival in a clinically relevant rhesus macaque model. DCreg expressed low MHC class II and costimulatory molecules, but comparatively high levels of programmed death ligand-1 (B7-H1), and were resistant to pro-inflammatory cytokine-induced maturation. They were infused intravenously (3.5-10 × 10(6) /kg), together with the B7-CD28 costimulation blocking agent CTLA4Ig, 7 days before renal transplantation. CTLA4Ig was given for up to 8 weeks and rapamycin, started on Day -2, was maintained with tapering of blood levels until full withdrawal at 6 months. Median graft survival time was 39.5 days in control monkeys (no DC infusion; n = 6) and 113.5 days (p < 0.05) in DCreg-treated animals (n = 6). No adverse events were associated with DCreg infusion, and there was no evidence of induction of host sensitization based on circulating donor-specific alloantibody levels. Immunologic monitoring also revealed regulation of donor-reactive memory CD95(+) T cells and reduced memory/regulatory T cell ratios in DCreg-treated monkeys compared with controls. Termination allograft histology showed moderate combined T cell- and Ab-mediated rejection in both groups. These findings justify further preclinical evaluation of DCreg therapy and their therapeutic potential in organ transplantation.
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Ezzelarab
authors.forename: A F
authors.initials: AF
authors.lastname: Zahorchak
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.forename: A E
authors.initials: AE
authors.lastname: Morelli
authors.forename: G
authors.initials: G
authors.lastname: Chalasani
authors.forename: A J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: F G
authors.initials: FG
authors.lastname: Lakkis
authors.forename: M
authors.initials: M
authors.lastname: Wijkstrom
authors.forename: N
authors.initials: N
authors.lastname: Murase
authors.forename: A
authors.initials: A
authors.lastname: Humar
authors.forename: R
authors.initials: R
authors.lastname: Shapiro
authors.forename: D K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000069594:Abatacept; D000818:Animals; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007674:Kidney Diseases / Q000276:immunology / Q000517:prevention & control*; D016030:Kidney Transplantation / Q000276:immunology*; D008253:Macaca mulatta; D008297:Male; D020123:Sirolimus / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D020123:Sirolimus
keywords: Costimulation blockade; dendritic cells; memory T cells; rapamycin; renal transplant; rhesus macaques