Treatment with mTOR inhibitors after liver transplantation enables a sustained increase in regulatory T-cells while preserving their suppressive capacity

Abstract

Background: The mammalian targets of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVR]) are used after transplantation for their immunosuppressive activity. Regulatory T-cells (Tregs) play a crucial role in immune tolerance. mTOR inhibitors appear to preserve Tregs, unlike Tacrolimus (Tac).

Aim: The aim of this study was to evaluate the number and function of Tregs in liver transplant recipients before and after conversion from Tac to mTOR inhibitors.

Methods: Fifteen patients with stable graft function where converted to SRL (n=5) or EVR (n=10). Tregs (CD4⁺ CD25⁺ FoxP3⁺ CD127^low) number and activity were analysed prospectively in blood cells using flow cytometry, and functional assay.

Results: Patients of both groups displayed a sustained rise in Treg levels after introduction of mTOR inhibitors (Treg levels at 3 months: 6.45±0.38% of CD4 T-cells, vs. baseline level of 3.61±0.37%, P<0.001; mean fold increase 2.04±0.73). In SRL group, 3-month Treg levels were 6.01±0.53 vs. 3.79±0.39; P=0.037, while in EVR group they were 6.63±0.67 vs. 3.54±0.51; P=0.001. By contrast, no statistical change was observed in an unconverted Tac control group. Tregs also preserved their functional ability to suppress activated T-cells.

Conclusion: These results suggest that mTOR inhibitors induce a significant increase in Tregs while maintaining suppressive activity after LT.

Keywords: Calcineurin inhibitor.; Liver; Regulatory T-cells; Transplantation; mTOR inhibitor.