The effects of immunosuppressive drugs on CD4(+) CD25(+) regulatory T cells: a systematic review of clinical and basic research

Abstract

Objective: To review the effects of different immunosuppressive drugs on proliferation and function of regulatory T cells (Tregs).

Methods: We searched MEDLINE, Embase (from inception to September 2009), and the Cochrane Library (Issue 4, 2009) for clinical and basic research about the effects of various immunosuppressive drugs on Tregs. Data were extracted and methodological quality was assessed by two independent reviewers. Outcome measures for clinical research included blood Tregs levels, acute rejection episodes, and graft function. Outcomes for basic research included percentage of Tregs proliferation, function, Tregs phenotype, and evidence for possible mechanisms. We analyzed data qualitatively.

Results: Forty-two studies, including 19 clinical trials and 23 basic studies, were included. The immunosuppressive drugs studied were calcineurin inhibitors (CNIs), Rapa, anti-metabolism drugs, IL-2 receptor-blocking antibodies, T-cell depleting antibodies, and co-stimulation blockade antibodies. Most of the studies were on Rapa and CNIs. Eight basic studies on Rapa and CNIs showed that Rapa could promote the proliferation and function of Tregs, while CNIs could not. Five clinical trials involving a total of 158 patients showed that patients taking Rapa had higher blood concentration of Tregs than patients taking CNIs, but no difference was found in graft function (6-42 months follow-up).

Conclusion: There is substantial evidence that Rapa favors Tregs survival and function. However, the higher numbers of blood Tregs in patients treated with Rapa do not show any association with better graft function. Larger clinical studies with longer follow-up are needed to more thoroughly assess the efficacy of immunosuppressive drugs on Tregs, and reveal whether a relationship exists between Tregs and graft function.