Effects of two classes of immunosuppressive agents, mTOR inhibitors vs. calcineurin inhibitors, on the generation and function of human alloreactive T helper cells (Th1, Th17 and Treg)

Successful transplantation requires the prevention of allograft rejection and complete reduction of the effects on the immune system by any immunosuppressive agent. The commonly immunosuppressive drugs used in clinical such as calcineurin inhibitor (tacrolimus, TAC) and mTOR inhibitor (sirolimus, SRL) affect naïve T cell differentiation and memory T cell expansion;; however, the biological and biochemical changes induced by these drugs on the generation and expansion of different subpopulations of T helper cells are not fully elucidated yet. CD4 positive (CD4+) T cells are known to orchestrate and regulate adaptive immune responses and play an important role in allograft rejection or tolerance. CD4+ T cells, upon activation and expansion, develop into different effector T helper cell subsets and produce distinct cytokine profiles and mediate separate effector functions. From a functional perspective, CD4+ T cells can be classified into effector T helper cells (Th1, Th2, Th17, Tfh) and regulatory T cells (Tregs). In the transplant setting, prevailing evidence shows that both effector Th1, Th17 cells and cytokines IFN-­, IL-­17 are involved in the process of allograft rejection whereas Treg and Th2 cells favor long-­term graft survival. The effects of Tacrolimus and Sirolimus on these subsets were studied because a balance between graft-­destructive effector T cells and graft-­protective regulatory T cells toward dominance of Tregs may promote clinical transplant tolerance. Therapies targeting inhibition of pathogenic effector T cells, promotion of Treg cells and directing against the mediators of intragraft inflammation may have profound effects on the rejection process and induce long-­term graft acceptance