Immunophenotyping of peripheral immunoregulatory as well as Th17A and Th22 cell subpopulations in kidney transplant recipients under belatacept or cyclosporine treatment.

OBJECTIVE: Regulatory Foxp3-expressing T cells (Tregs), IL-10-producing B cells (Bregs), and IDO-expressing dendritic cells (DCregs) downregulate inflammatory processes and induce peripheral tolerance, while Th17A and Th22 cell subpopulations are of proinflammatory nature. The aims of the study were to characterize and to enumerate peripheral Tregs, Bregs, and DCregs and Th17A and Th22 cell subpopulations in kidney transplant recipients (KTRs) under belatacept or cyclosporine treatment. METHODS: Forty-one KRT patients (30 under belatacept treatment and 11 under cyclosporine treatment) and 26 healthy donors (HDs) were included in the study. CD19(+)-expressing peripheral B lymphocytes were purified by positive selection. IL-10-producing B cells, CD4(+)/CD25(high)Foxp3(+), and CD8(+)/CD28(-)Foxp3(+) Tregs, CCR6(+)/CD123(+)/IDO(+) DCs, as well as Th17A and Th22 cell subpopulations were quantitated by flow cytometry. RESULTS: Of the IL-10-producing Bregs, CD19(+)/CD24(high)/CD38(high)/CD5(+), CD19(+)/CD24(high)/CD38(high)/CD10(+), CD19(+)/CD24(high)/CD38(high)/CD20(+), and CD19(+)/CD24(high)/CD38(high)/CD27(-) had significant higher frequency in patients under belatacept treatment when compared with those under cyclosporine. Only CD19(+)/CD24(high)/CD38(high)/CD27(+) and CD19(+)/CD24(high)/CD38(high)/CXCR7(+) cells had significant higher frequency in patients under cycloporine treatment when compared to those under belatacept. The percentages of IDO-expressing pDC, CD4(+)/CD25(high)Foxp3(+), and CD8(+)/CD28(-)Foxp3(+) were significantly higher in the belatacept group when compared the cyclosporine one, while Th17A and Th22 cells had significant higher frequency in the latter group. CONCLUSION: Belatacept seems to maintain and enhance, at least systemically, a tolerant profile to renal allograft in transplant recipients by means of higher circulatory frequencies of regulatory B, T and pDC subpopulations.

Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase II study.

Kidney transplant recipients who switched from a calcineurin inhibitor (CNI) to belatacept demonstrated higher calculated glomerular filtration rates (cGFRs) at 1 year in a Phase II study. This report addresses whether improvement was sustained at 2 years in the long-term extension (LTE). Patients receiving cyclosporine or tacrolimus were randomized to switch to belatacept or continue CNI. Of 173 randomized patients, 162 completed the 12-month main study and entered the LTE. Two patients (n = 1 each group) had graft loss between Years 1-2. At Year 2, mean cGFR was 62.0 ml/min (belatacept) vs. 55.4 ml/min (CNI). The mean change in cGFR from baseline was +8.8 ml/min (belatacept) and +0.3 ml/min (CNI). Higher cGFR was observed in patients switched from either cyclosporine (+7.8 ml/min) or tacrolimus (+8.9 ml/min). The frequency of acute rejection in the LTE cohort was comparable between the belatacept and CNI groups by Year 2. All acute rejection episodes occurred during Year 1 in the belatacept patients and during Year 2 in the CNI group. There were more non-serious mucocutaneous fungal infections in the belatacept group. Switching to a belatacept-based regimen from a CNI-based regimen resulted in a continued trend toward improved renal function at 2 years after switching.