Belatacept Does Not Inhibit Follicular T Cell-Dependent B-Cell Differentiation in Kidney Transplantation

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.

T Follicular Helper Cells As a New Target for Immunosuppressive Therapies

“…A recent study from our group demonstrated that Tac had a small inhibitory effect on Tfh-cell generation in vitro and could partially prevent Tfh-cell activation. The production of IL-21 was incompletely inhibited by high concentrations of Tac, which may be why the remaining activated Tfh cells retained the potential capacity to assist B cells ( 60 ). In another study, methylprednisolone treatment of patients with systemic lupus erythematosus was found to reduce the number of peripheral CD4 + CXCR5 + PD-1 + T cells, but without any evidence of altered Tfh function ( 61 ).…”

“…In kidney transplant patients, we found that belatacept partially inhibited Tfh-cell activation; the remaining activated Tfh cells were able to provide B cell help. Belatacept is less potent in vitro than Tac in inhibiting Tfh-cell-dependent plasmablast formation ( 60 ). Based on these preliminary data, it seems that human circulating Tfh cells after transplantation are less susceptible to costimulation blockade than mouse Tfh cells.…”

Commentary: Belatacept Does Not Inhibit Follicular T Cell-Dependent B-Cell Differentiation in Kidney Transplantation

“…Disrupting this process could be key to developing more effective therapies for AMR. The recent study by de Graav et al describes the effects of belatacept and tacrolimus on the process of Tfh cell–dependent B-cell differentiation ( 1 ). Their data provide important insights into the isolated effects of tacrolimus and belatacept in vitro , but do not demonstrate that belatacept fails to inhibit Tfh cell-dependent B-cell differentiation in kidney transplantation, as the article title suggests.…”

Memory T‐cell exhaustion and tolerance in transplantation

“…[97][98][99] However, it was initially unclear as to whether belatacept was functioning directly on B cells or through a secondary impact on Tfh cells. [97][98][99] However, it was initially unclear as to whether belatacept was functioning directly on B cells or through a secondary impact on Tfh cells.…”

“…Belatacept has been shown to be effective at abolishing germinal centers and mitigating alloantibody responses in allosensitized patients. [97][98][99] However, it was initially unclear as to whether belatacept was functioning directly on B cells or through a secondary impact on Tfh cells. 100 In an evaluation of peripheral circulating Tfh cells, belatacept therapy was shown to be on par with traditional calcineurin inhibition in mitigating influence of Tfh on B-cell differentiation post-transplant.…”