Impact of immunosuppressive drugs on CD4+CD25+FOXP3+ regulatory T cells: does in vitro evidence translate to the clinical setting?

Success of solid-organ transplantation requires the continuous administration of immunosuppressive drugs to prevent graft rejection. The currently prescribed immunosuppressive medication targets the immune system in a nonspecific fashion, leading to debilitating side effects that diminish patient survival and quality of life. Therefore, it is important to minimize immunosuppression, but this requires the development of alternative therapeutic strategies to induce and maintain transplant tolerance. One such strategy would be to allow and facilitate the induction of alloantigen-specific immune regulation by regulatory T cells (Treg). Recent experimental studies indicate that several commonly used immunosuppressive drugs have detrimental effects on the induction and function of Treg, whereas other drugs appear to spare these cells or may even be beneficial. These differential effects may be explained by differences in signaling pathways between Treg and effector T cells. In this review, we provide a comprehensive overview of the current literature on the effects of immunosuppressive drugs on CD4+CD25+FOXP3+ Treg and discuss whether these in vitro data are substantiated by in vivo evidence from the clinic. A greater understanding of the impact of immunosuppression on Treg may help to create future opportunities to manipulate the host allo-immune response and achieve operational tolerance in transplantation.