Since the costimulatory inhibitor belatacept effectively blocks T-B cell interaction in animal transplant models, we studied the functional follicular T helper cells (TFH)-B cell interaction in belatacept-treated patients to determine the effects of this drug in human kidney transplantation (KT).

The presence of CXCR5+PD-1+CD4+ TFH cells, CD19+CD27+CD38++ plasmablasts and CD19+CD24++CD38++ transitional B cells was assessed in belatacept- and tacrolimus-treated patients (n=40), and in vitro after donor antigen re-stimulation in the presence and absence of therapeutic concentrations of belatacept (10 [micro]g/mL) or tacrolimus (10 ng/mL). PBMCs were obtained 3 months after KT or during an acute rejection episode (before additional therapy). The proportion of TFH-cells and their allogeneic IL-2 and IL-21 production were measured as well as the differentiation of B cells into TNFα-producing effector plasmablasts and transitional IL-10+ regulatory B cells (Bregs).

In belatacept-treated patients, the frequency of circulating TFH cells was low before KT (0.6 cells/[micro]L), and did not change after. The number of circulating plasmablasts and transitional B cells dropped under belatacept treatment (from 0.3 to 0.2 cells/[micro]L, p=0.006, and from 1.5 cells/[micro]L to 0.2 cells/[micro]L, p=0.001, respectively). Similar observations were made for tacrolimus-treated patients. After in vitro re-stimulation with donor antigen, a 10-fold increase of TFH cells was observed, which was 30% inhibited by belatacept, p=0.001, and 50% by tacrolimus, p<0.001. Intracellular IL-2 and IL-21 production by these T cells was not suppressed by belatacept or tacrolimus. Interestingly, in belatacept-treated patients, during rejection (n=11) a higher proportion of donor-antigen re-stimulated TFH cells produced IL-21 than in stable patients (n=9), 39% vs. 22%, respectively, p=0.01. Stimulated B cells differentiated into TNFα-producing plasmablasts, a process not inhibited by belatacept, but only by tacrolimus. Unlike tacrolimus, however, belatacept favored the differentiation into IL-10+ Bregs. No differences were found in B cell differentiation between rejectors and non-rejectors.

In short, in vitro belatacept favors a regulatory profile of B cells, but fails to inhibit the donor-reactive TFH-B cell interaction after human KT.

CITATION INFORMATION: de Graav G, Hesselink D, Dieterich M, Kraaijeveld R, Weimar W, Baan C. Belatacept Does Not Inhibit Plasmablast Formation Supported by Follicular T Helper Cells, but Favors the Development of Transitional Regulatory B Cells in Kidney Transplant Patients. Am J Transplant. 2016;16 (suppl 3).

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