Sirolimus vs mycophenolate moftile in Tacrolimus based therapy following induction with Antithymocyte globulin promotes regulatory T cell expansion and inhibits RORγt and T-bet expression in kidney transplantation

Background: Accumulating evidence suggests that regulatory T cells (Tregs) have a crucial role in immune tolerance and long-term graft survival. However, the influence of immunosuppressive drugs on the level of Tregs has not been fully understood. Therefore we prospectively compare the effect of two different calcineurin inhibitor (CNI)-based immunosuppression protocols on Tregs frequencies and expression of regulatory and effector T cell-related genes in renal transplant recipients. Methods: The study included 24 renal transplant recipients who received induction therapy (Antithymocyte globulin) and were on triple immunosuppressive therapy so that one group was on Tacrolimus (Tac), mycophenolate moftile (MMF) and prednisolone (P) whereas another group was on Tac, Sirolimus (SRL) and P. The frequency of circulating Treg cells was analyzed by flow cytometry before and 4 months after transplantation. Also, the mRNA expression of FOXP3, T-bet, GATA3 and ROR gamma t was examined by quantitative RT-PCR before and 4 months after transplantation. Results: Compared to baseline, the frequency of CD4(+) CD25(+) FOXP3(+) Treg cells was significantly increased in the all patients following transplantation. Patients who received Tac/MMF had significantly higher CD4(+) CD25(+) FOXP3(+) Treg cells compared to patients who received Tac/SRL. There was no a significant difference in the frequency of CD3(+)CD8(+) CD28(-) Tregs between two different calcineurin inhibitor (CNI)-based immunosuppression protocols. FOXP3 mRNA levels in the patients who received Tac/MMF were increased 4 months after transplantation and the expression was significantly higher than patients who received Tac/SRL. On the other hand, T-bet and ROR gamma t expression levels were significantly lower in the Tac/SRL group in comparison to Tac/MMF group. We did not observe any significant difference in GATA3 mRNA level between the two groups. Conclusions: Our results suggest that although Tac/MMF-containing immunosuppressive regimen could significantly increase the frequency of CD4(+) CD25(+) FOXP3(+) Tregs, unlike to Tac/SRL-containing regimen, it could not significantly decrease the expression levels of ROR gamma t and T-bet.