Influence of immunosuppressive drugs on the development of CD4(+)CD25(high) Foxp3(+) T cells in liver transplant recipients

Abstract

Introduction: Many studies suggest that CD4(+)CD25(high) T regulatory cells (Tregs) have a crucial role in downregulating the immune response to alloantigens. In this study, we investigated the possible influence of immunosuppressive therapy, including rapamycin and calcineurin inhibitors (CNIs; tacrolimus), on level of Tregs in liver allograft recipients.

Materials and methods: We assessed 47 liver transplant recipients with stable liver function for ≥2 years, dividing them into 2 groups: Patients receiving rapamycin (n = 15), and those receiving tacrolimus (n=32). Thirty-eight, age-matched healthy subjects were used as normal controls. We examined the expression of CD4, CD25, and Foxp3 in peripheral blood T cells. Flow cytometry was performed with a FACSCalibur instrument with data analysis using Cell Quest software.

Results: Rapamycin significantly increased the prevalence of Tregs, including the percentage of CD4(+)CD25(high) T cells in total lymphocytes and among total CD4(+) T cells, compared with the healthy subjects and the CNI group. The prevalence of Tregs in the CNIs group was significantly lower than that of controls. Foxp3 was expressed in >95% of CD4(+)CD25(high)T cells, whereas it was in <20% of CD4(+)CD25(low) T cells and not expressed among CD4(+)CD25(-) T cells.

Conclusions: Immunosuppressive therapy (rapamycin or CNIs) may have a different roles in tolerance induction among liver transplant recipients. Namely, rapamycin promoted the induction of a profile consistent with alloantigen tolerance; CNIs hampered this progression.