Suppressive Effect of 1α,25-Dihydroxyvitamin D3 on Th17-Immune Responses in Kidney Transplant Recipients With Tacrolimus-Based Immunosuppression

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Abstract

Background

The aim of this study was to investigate whether 1α,25-dihydroxyvitamin D3 can regulate Th17-related immune responses in kidney transplant recipients (KTRs) being treated with tacrolimus (Tac)-based immunosuppression.

Methods

First, we evaluated the effect of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on Th17-immune responses in an in vitro study using peripheral blood mononuclear cells (PBMCs) from healthy volunteers or KTRs. Next, we investigated mammalian target of rapamycin/STAT3 signaling as a mechanism by which 1,25(OH)2D3 exerted its effect on T cells using the Jurkat cell line. Third, we investigated Th17-cytokine levels or Th17 cell percentage in PBMCs according to the serum 25-hydroxyvitamin D (25(OH)D) level in 81 KTRs, and we performed a prospective study to assess whether 1,25(OH)2D3 (calcitriol) treatment decreased Th17 cytokine levels (IL-17, IL-22) in 42 KTRs.

Results

In the in vitro study, we observed that the addition of 1,25(OH)2D3 to Tac significantly inhibited the appearance of IL-17-positive cells in culture. The expression of IL-17 and IL-22 messenger RNA in PBMCs was also decreased by the addition of 1,25(OH)2D3. In the Jurkat cell line, the mTOR/STAT3 pathway was further downregulated with the addition of 1,25(OH)2D3 to Tac. In the 81 KTRs, the 25(OH)D level was inversely correlated with the Th17 cytokine levels or the proportion of Th17 cell out of CD4+ T cells. Treatment with calcitriol for 6 months significantly decreased Th17 cytokine levels compared with the baseline values in another 42 KTRs.

Conclusions

Treatment with 1,25(OH)2D3 may have immunologic benefits by effectively suppressing the Th17-related immune responses in KTRs on Tac-based immunosuppression.

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