Reduced numbers of blood natural regulatory T cells in stable liver transplant recipients with high levels of calcineurin inhibitors

INTRODUCTION: In solid organ transplantation, most efforts are directed to achieve a state of tolerance and reduce the immunosuppressive load. Since the liver is thought to be more tolerogenic than other grafts, we examined the impact of various immunosuppressant regimens on induction of CD4+CD25(high)FOXP3+ regulatory T cells (Tregs). MATERIALS AND METHODS: We divided 35 liver transplant recipients with stable function and free of rejection episodes for at least 8 years into two main groups according to the blood levels of calcineurin inhibitors (CNIs) at the time of the study: 15 patients showing high concentrations of either cyclosporine or FK506 (high CNI: cyclosporine >80 ng/mL or FK506 >6 ng/mL) and another 20 patients with low levels (low CNI). Thirty-eight age-matched healthy subjects were used as normal controls. RESULTS: Circulating T cells of a regulatory phenotype (CD4+CD25(high)FoxP3+) were decreased in peripheral blood of liver transplant recipients compared with healthy donors. Importantly, those patients with high CNI demonstrated significantly lower levels of Tregs compared with those with low CNI. Furthermore, low CNI recipients showed no significant difference from healthy donors. CONCLUSIONS: A high load of immunosuppression may hamper the induction of tolerance in liver transplantation through interference with induction of Tregs in stable liver transplant recipients. Thus, quantification of blood Tregs may help to decide whether to lower immunosuppression.