Preferential increase in memory and regulatory subsets during T-lymphocyte immune reconstitution after Thymoglobulin induction therapy with maintenance sirolimus vs cyclosporine

Abstract

Background: Sirolimus maintenance therapy with Thymoglobulin induction is a promising regimen that may preserve renal function. Data are lacking, however, about the immunologic effects of combined Thymoglobulin-sirolimus.

Methods: In a 12-month, prospective, randomised, open-label, single-centre pilot study, de novo deceased-donor kidney transplant patients were randomised to receive cyclosporine or sirolimus, with Thymoglobulin induction, mycophenolate mofetil and corticosteroids. Flow cytometry analysis of peripheral blood was used to evaluate immune reconstitution.

Results: Nineteen patients were recruited (sirolimus 9, cyclosporine 10). Reconstitution of the CD4(+) T-lymphocyte subset was significantly lower with sirolimus versus cyclosporine over year 1, but CD8(+) reconstitution did not differ significantly between groups. The proportion of naïve CD4(+) T-lymphocytes showed an initial decrease with sirolimus versus cyclosporine. Naïve CD8(+) T-lymphocytes increased versus baseline in the cyclosporine cohort at months 1 and 3, but remained unchanged with sirolimus. Memory CD4(+) T-lymphocytes occurred more frequently in sirolimus- versus cyclosporine-treated patients during year 1. The proportion of memory CD8(+) T-lymphocytes decreased at months 1 and 3 compared to baseline in the CsA arm, but did not change in the sirolimus cohort. By month 12, the proportion of both naïve and memory CD4(+) and CD8(+) T-lymphocytes had become similar with sirolimus or cyclosporine. There were fewer naïve B-lymphocytes in the sirolimus cohort and more CD19(-)IgD(+/-)CD27(+) memory B-lymphocytes.

Conclusions: In this small population, homeostatic reconstitution after Thymoglobulin induction showed disproportionately high recovery of memory T-lymphocyte subsets during sirolimus therapy, which may explain the higher rejection rate seen with sirolimus versus cyclosporine following kidney transplantation.