Number of peripheral blood regulatory T cells and lymphocyte activation at 3 months after conversion to mTOR inhibitor therapy

Abstract

Background: Mammalian target of rapamycin (mTOR) inhibitors are effective for induction and maintenance of regulatory T cells (Tregs).

Objective: To assess the effects of conversion from calcineurin inhibitors (CNIs) to mTOR on the number of circulating Tregs and lymphocyte activation.

Patients and methods: In 18 renal transplant recipients receiving CNI therapy (cyclosporine in 9, and tacrolimus in 9), treatment was converted to mTOR inhibitors (everolimus in 14, and rapamycin in 4). Peripheral blood samples were obtained before and 3 months after conversion. The number of circulating Tregs was measured using flow cytometry, and defined as CD4+/CD25high/CD127low/CD27+/CD62L+/CD45RO+/Foxp3+. Lymphocyte activation was assessed indirectly according to production of intracellular adenosine triphosphate (iATP) on polyclonal activation using a phytohemaglutinin assay (Immuknow; Cylex, Inc, Columbia, Maryland).

Results: In 15 patients (83.3%), the absolute number of Tregs increased significantly (P=.001) after conversion (median, 16.35 cells/mm3; 95% confidence interval [CI], 13.97-21.94) vs 3 months after conversion (32.03 cells/mm3; 95% CI, 26.25-41.66). The iATP production decreased from 326 ng/mL (95% CI, 302-419) to 248 ng/mL (95% CI, 196-318; P=.02), and increased in 4 patients (22.22%). No significant correlation was demonstrated between Treg concentration and change in iATP production. No rejection episodes were reported during follow-up.

Conclusions: Despite the small number of patients in whom therapy was converted from CNI inhibitors to mTOR inhibitors, the data suggest an increase in the absolute number of Tregs after conversion. In addition, the concentration of activated peripheral CD4+ T cells decreased to nearly that associated with risk of infection due to overimmunosuppression.