Background: Regulatory immune cells are promising therapeutic agents to promote immunosuppressive drug minimization/withdrawal in organ transplantation. Dendritic cells (DC) are innate immune antigen (Ag)-presenting cells with inherent tolerogenic properties. Regulatory DC (DCreg) promote transplant tolerance following their adoptive transfer in rodents, and induce Ag-specific T cell tolerance in humans.
Methods: We examined the influence of DCreg generated from cytokine-mobilized donor blood monocytes in vitamin D3 and IL-10, on renal allograft survival in a clinically-relevant non-human primate (rhesus macaque) model. Immunosuppression comprised costimulation blockade and rapamycin maintenance. Graft function was determined by creatinine level, body weight and urinary protein/creatinine ratio. T cell and alloAb responses to donor and 3rd party were monitored.
Results: DCreg expressed low levels of MHCII and costimulatory molecules but comparatively high levels of programmed death ligand-1 (B7-H1), and were resistant to maturation in response to pro-inflammatory cytokines in vitro. They were infused intravenously (3.5-10×106/kg), together with the B7-CD28 costimulation blocking agent CTLA4Ig, 7 d before transplantation. CTLA4Ig was administered for up to 8 weeks and rapamycin started on d-1 was maintained with tapering of blood levels until full withdrawal at 6 months. Median graft survival time was 39.5 d in control monkeys (no DC infusion; n=6) and 113.5 d (p< 0.05) in DCreg-treated animals (n=6). No adverse effects were associated with DCreg infusion and there was no evidence of host sensitization based on circulating anti-donor alloantibody levels. Immunologic monitoring revealed regulation of memory CD95+ memory T cells and reduced effector memory/regulatory T cell ratios in DCreg-treated monkeys compared with controls. Termination allograft histology showed evidence of moderate combined T cell- and Ab-mediated rejection in both groups.
Conclusion: These findings justify further pre-clinical evaluation of DCreg therapy and underscore the therapeutic potential of these regulatory innate immune cells in organ transplantation.
To cite this abstract in AMA style:Ezzelarab M, Zahorchak A, Lu L, Adrian M, Fadi L, Demetris J, Humar A, Shapiro R, Murase N, Wijkstrom M, Cooper D, Thomson A. Regulatory Dendritic Cells (DCreg) Prolong Kidney Allograft Survival in Non-Human Primates When Combined with Costimulation Blockade and Rapamycin [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/regulatory-dendritic-cells-dcreg-prolong-kidney-allograft-survival-in-non-human-primates-when-combined-with-costimulation-blockade-and-rapamycin/. Accessed January 22, 2021.
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