Ezzelarab M B, Raich-Regue D, Lu L, Zahorchak A F, Perez-Gutierrez A, Humar A, Wijkstrom M, Minervini M, Wiseman R W, Cooper D K C, Morelli A E, Thomson A W
Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Am J Transplant. 2017 Jun;17(6):1476-1489. doi: 10.1111/ajt.14182. Epub 2017 Feb 2.
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 × 10 /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.
对啮齿动物进行自体调节性树突状细胞（DCreg；未负载或负载供体抗原[Ag]）的全身给药，可延长同种异体移植物的存活时间并促进移植耐受。在此，我们证明，预先加载来自同种异体外周血单个核细胞膜囊泡的非人灵长类动物（NHP）单核细胞衍生的DCreg在体外可诱导T细胞对供体同种异体抗原（alloAg）低反应性。在对接受共刺激阻断（细胞毒性T淋巴细胞抗原4免疫球蛋白[CTLA4] Ig）和逐渐减量雷帕霉素治疗的恒河猴进行MHC不匹配肾移植前1天，静脉注射这些负载供体alloAg的自体DCreg（1.4 - 3.6×10⁶/kg）。移植物中位存活时间从39.5天（未输注DCreg；n = 6个历史对照）和使用未负载DCreg对照时的29天（n = 2）延长至负载供体Ag的DCreg时的56天（n = 5），这与宿主CD4和CD8 T细胞对供体Ag反应的调节以及全身IL - 17产生的减弱有关。直到停用CTLA4 Ig后才检测到循环抗供体抗体（Ab）。一只接受负载供体Ag的DCreg治疗的猴子在移植后525天（停用免疫抑制后160天）因抗供体Ab逐渐升高而排斥其移植物。这些发现表明，在采用最小免疫抑制药物方案给药时，负载供体Ag的自体DCreg输注对NHP移植物存活有适度但无统计学意义的有益作用。
