Effect of Mammalian Target of Rapamycin Inhibition on Activated Regulatory T-Cell Expansion in Kidney Transplantation

Abstract

The mammalian target of rapamycin (mTOR) plays a critical role in the host immune response in organ transplantation. This study evaluates the regulatory benefits of mTOR inhibitors in kidney transplant recipients (KTRs). The mTOR-dependent immune-regulating effects in KTRs were evaluated by examining T-cell subsets among peripheral blood mononuclear cells from 79 KTRs. Recipients included an early introduction of everolimus (EVR) and reduced-exposure tacrolimus group (n=46) and a standard tacrolimus-based without EVR (non-EVR) group (n=33). Trough concentrations of tacrolimus at 3 months and 1 year were significantly lower in the EVR group than the non-EVR group (both P < .001). In addition, the respective proportions of patients without estimated glomerular filtration rate < 20% in the EVR and non-EVR groups were 100% and 93.3% at 1 year, 96.3% and 89.7% at 2 years, and 96.3% and 89.7% at 3 years after blood collection, respectively (P=.079). The frequencies of CD3+ T cells and CD4+ T cells among peripheral blood mononuclear cells were comparable between groups. Total CD25highCD127-CD4+ regulatory T (Treg) cells were similar in the EVR and non-EVR groups. In contrast, circulating CD45RA-CD25highCD127-CD4+ activated Treg cells were significantly higher in the EVR group (P= .008). These results suggest that the early introduction of mTOR benefits long-term kidney graft function and circulating activated Treg-cell expansion in KTRs.