Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Front Immunol. 2018 Feb 19;9:250. doi: 10.3389/fimmu.2018.00250. eCollection 2018.
Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4 T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4 T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4CTLA4, but not CD4CTLA4 T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4CTLA4, but not CD4CTLA4 T cells following allo-stimulation, associated with a significant reduction in the CD4CTLA4/CD4CTLA4 T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4CTLA4 T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4CTLA4/CD4CTLA4 T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4CTLA4 T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.
移植前供体来源的调节性树突状细胞 (DCreg) 输注可显著延长非人类灵长类动物的肾移植存活期。这与宿主供体反应性 T 细胞中免疫调节分子细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）和程序性细胞死亡蛋白 1（PD1）的表达增强有关。在啮齿动物和人类中，CD28 共刺激途径阻断与融合蛋白 CTLA4:Ig（CTLA4Ig）相关联，可减少调节性 T 细胞（Treg）的分化和发育。我们假设，在接受 CTLA4Ig 治疗的输注了 DCreg 的受者中，供体反应性 CD4 T 细胞中 CTLA4 的上调可能与具有 Treg 表型的供体反应性 CD4 T 细胞的更高发生率有关。在正常恒河猴中，同种异体刺激的 CD4CTLA4，但不是 CD4CTLA4 T 细胞表现出调节表型，而与 PD1 表达无关。CTLA4Ig 显著降低了同种异体刺激后 CD4CTLA4，但不是 CD4CTLA4 T 细胞的发生率，与 CD4CTLA4/CD4CTLA4 T 细胞比值的显著降低有关。在 CTLA4Ig 治疗的肾移植受者猴中，循环供体反应性 CD4CTLA4 T 细胞明显减少。相比之下，在输注了 DCreg 的 CTLA4Ig 治疗猴中，没有观察到这种减少。平行地，在没有输注 DCreg 的移植物受者中，供体反应性 CD4CTLA4/CD4CTLA4 T 细胞比值显著降低，但在给予 DCreg 的受者中增加。这些观察结果表明，移植前 DCreg 输注可促进和维持移植后具有调节表型的供体反应性 CD4CTLA4 T 细胞，即使在存在 CD28 共刺激阻断的情况下也是如此。
