Abstract
Humoral alloreactivity has been recognized as a common cause of kidney transplant dysfunction. B-cell activation, differentiation, and antibody production are dependent on IL-21+CXCR5+follicular T-helper (Tfh) cells. Here, we studied whether belatacept, an inhibitor of the costimulatory CD28-CD80/86-pathway, interrupts the crosstalk between Tfh- and B-cells more efficiently than the calcineurin inhibitor tacrolimus. The suppressive effects of belatacept and tacrolimus on donor antigen-driven Tfh–B-cell interaction were functionally studied in peripheral blood mononuclear cells from 40 kidney transplant patients randomized to a belatacept- or tacrolimus-based immunosuppressive regimen. No significant differences in uncultured cells or donor antigen-stimulated cells were found between belatacept- and tacrolimus-treated patients in the CXCR5+Tfh cell generation and activation (upregulation of PD-1). Belatacept and tacrolimus in vitro minimally inhibited Tfh-cell generation (by ~6–7%) and partially prevented Tfh-cell activation (by ~30–50%). The proportion of IL-21+-activated Tfh-cells was partially decreased by in vitro addition of belatacept or tacrolimus (by ~60%). Baseline expressions and proportions of activated CD86+ B-cells, plasmablasts, and transitional B-cells after donor antigen stimulation did not differ between belatacept- and tacrolimus-treated patients. Donor antigen-driven CD86 upregulation on memory B-cells was not fully prevented by adding belatacept in vitro (~35%), even in supratherapeutic doses. In contrast to tacrolimus, belatacept failed to inhibit donor antigen-driven plasmablast formation (~50% inhibition vs. no inhibition, respectively, p < 0.0001). In summary, donor antigen-driven Tfh-B-cell crosstalk is similar in cells obtained from belatacept- and tacrolimus-treated patients. Belatacept is, however, less potent in vitro than tacrolimus in inhibiting Tfh-cell-dependent plasmablast formation.
Highlights
B-cells and antibodies against the allograft are increasingly recognized to contribute to alloreactivity and subsequent graft failure after kidney transplantation under the currently used calcineurin inhibitor (CNI)-based immunosuppressive regimen [1,2,3,4,5,6,7]
The survival of the potentially immune regulatory IL-10+ transitional B-cells was, not affected by belatacept, while this was diminished by tacrolimus
In PBMCs from three belatacept-treated and three tacrolimus-treated patients, the ICOS-ICOSL, PD-1-PD-L1, and the CD40L-CD40 pathways were studied after donor antigen stimulation Expressions of all surface molecules, except for CD28 and ICOSL, were increased on Tfh and B-cells after donor antigen stimulation (Figures S4A,C in Supplementary Material)
Summary
B-cells and antibodies against the allograft are increasingly recognized to contribute to alloreactivity and subsequent graft failure after kidney transplantation under the currently used calcineurin inhibitor (CNI)-based immunosuppressive regimen [1,2,3,4,5,6,7]. Belatacept, or the lower affinity version abatacept (CTLA4 Immunoglobulin), inhibited germinal center formation, clonal B-cell expansion, IL-21 production, and the development of donor-specific anti-human leukocyte antigen antibodies (DSA) [14, 23]. These findings were in line with observations from a large randomized, controlled trial in kidney transplant patients where the belatacept-based regimen resulted in a significantly lower prevalence of DSA than the cyclosporine A (CsA)-based regimen at 7 years after transplantation: 4.6 vs 17.8%, respectively [24]. In all these clinical studies, belatacept was combined with other immunosuppressive drugs: in the BENEFIT and BENEFIT-EXT trials belatacept was combined with mycophenolate mofetil (MMF) and prednisone, and in the animal studies, belatacept was combined with either sirolimus or T-cell-depleting antibodies [14, 23,24,25]
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