Triptolide-Conditioned Dendritic Cells Induce Allospecific T-Cell Regulation and Prolong Renal Graft Survival

Abstract

ABSTRACTBackground: Previous studies show that triptolide (TPT), a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, inhibits dendritic cell (DCs) maturation. Whether TPT-conditioned DCs (TPT-DCs) may regulate allospecific immune responses remains unclear. In this study, we investigated the effects of TPT on allostimulatory function and phenotype of rat bone marrow-derived DCs (BMDCs). Methods: Brown Norway rats BMDCs were cultured with or without TPT and then stimulated with lipopolysaccharide (LPS). IL-10 in supernatants was quantitatively measured, and the cells were analyzed by flow cytometry and used as stimulators in mixed leukocyte reaction in which naive Lewis rat T lymphocytes were used as responders. The tolerogenic potential of TPT-BMDCs was evaluated in vivo in a rat model of MHC fully mismatched kidney transplantation. Results: After treatment with TPT, BMDCs remained immature with low expression of CD80 and CD86 in the presence of LPS. At low concentrations of TPT (1 and 2.5 nM), BMDCs produced higher levels of IL-10 than the untreated cells (431 and 205.4 pg/ml, respectively, vs. 122.9 pg/ml, p < .05). T cells cocultured with TPT-BMDCs were hyporesponsive in allogeneic mixed lymphocyte reaction. The CD25+foxp3+Treg cell populations increased from 19.9% to 29.7% in the coculture system. Without immunosuppressive therapy, infusion of TPT-BMDCs in recipients before transplantation prolonged rat kidney allograft survival (18.8 ± 1.30 days). Conclusions: Our findings demonstrate that TPT inhibits the maturation and allogenicity of BMDCs and promotes the expansion of CD25+foxp3+ regulatory T cells. It suggests that TPT-DCs are potentially useful for preventing kidney transplant rejection.