Abstract
BackgroundWe previously reported that tacrolimus (Tac) does not decrease T helper 17 cells (Th17) response in kidney transplantation. In this study, we evaluated whether Resveratrol (Resv) has immunosuppressive effects by decreasing Th17 responses in Tac-based immunosuppression.MethodsWe investigated the effects of Resv under Tac-treatment conditions, on CD4+ T cell differentiation to Th17 cells in peripheral blood mononuclear cells (PBMCs), and proliferation of CD4+ T cells co-cultured with human renal proximal tubular epithelial cells (HRPTEpiCs). The effects of Resv on Th17 cells were tested in the murine skin transplant model.ResultsIn PBMCs, Tac did not but combination of Tac and Resv further suppressed Th17 immune response. In the co-culture study, combination of Resv to Tac significantly decreased HRPTEpiC-induced T cell proliferation compared to Tac alone. Resv treatment in the Jurkat cell induced the expression of AMP-activated protein kinase and suppressed the expression of mammalian target of rapamycin (mTOR), suggesting blocking Th17 pathway by Resv. In the murine skin transplant model, combination of Resv to Tac significantly prolonged skin graft survival accompanied by the suppression of Th17 cells, compared to either the Tac-alone or control groups.ConclusionThe results of our study suggest that Resv provides additional immunosuppressive effects to Tac by suppressing effector CD4+ T cells, especially Th17 cells, in the transplantation setting.
Highlights
We previously reported that tacrolimus (Tac) does not decrease T helper 17 cells (Th17) response in kidney transplantation
[1] Out of various CD4+ T cell subsets, the activation of Th1 and Th17 cells has most commonly been reported to be associated with the development of allograft rejection in solid organ transplantation (SOT), [2,3,4,5] and we reported that Th17 cells and their associated cytokines play a significant role in the development of acute and chronic allograft rejection. [1, 4,5,6,7,8,9,10]
Doh et al BMC Complementary and Alternative Medicine (2019) 19:54 revealed its immune modulating effects in various immune diseases that primarily depend on Th17 immune responses. [18,19,20] It is effective modulator of mammalian target of rapamycin signaling, which plays an important role in the regulation of Th17 cell differentiation. [21]
Summary
We previously reported that tacrolimus (Tac) does not decrease T helper 17 cells (Th17) response in kidney transplantation. Methods: We investigated the effects of Resv under Tac-treatment conditions, on CD4+ T cell differentiation to Th17 cells in peripheral blood mononuclear cells (PBMCs), and proliferation of CD4+ T cells co-cultured with human renal proximal tubular epithelial cells (HRPTEpiCs). The aim of this study is to investigate the effect of Resv on Th17 immune responses when added to Tac. The aim of this study is to investigate the effect of Resv on Th17 immune responses when added to Tac To this end, we performed an in vitro study using CD4+ T cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy volunteers, and human renal proximal tubular epithelial cells (HRPTEpiCs) An in vivo study using a skin allograft mouse model was carried out
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