Belatacept is the first clinically approved transplant immunosuppressant based on costimulatory blockade (CoB). Kidney transplant recipients treated with belatacept had improved long-term renal function, albeit with increased rates of acute rejection. This CoB-resistant transplant rejection may be mediated by alloreactive T cells activated by secondary costimulatory molecules left untargeted by belatacept. We therefore examined whether secondary costimulatory receptor antagonists could synergize with traditional CoB to prolong transplant survival. Results: We first performed an in vivo mixed lymphocyte reaction using CFSE-labeled C57BL/6 splenocytes transferred into irradiated BALB/c hosts. After 3 days, splenocytes were harvested and alloproliferation was determined by assessment of CFSE dilution. The mice were treated with traditional CoB (CTLA-4Ig+ΑCD154) alone or CoB combined with a secondary costimulatory molecule antagonist: Α41BBL, ΑCD70, ΑICOSL or ΑOX40L. Both CoB+ΑICOSL and CoB+ΑOX40L suppressed alloproliferation compared to CoB alone. However, only combined CoB+ΑOX40L significantly prolonged MHC-mismatched murine skin graft survival compared to CoB alone (MST= 130 vs. 20 days, p<0.01). We next translated our findings to a clinically-relevant rhesus macaque renal transplant system. Treatment with combined belatacept+ΑOX40L markedly prolonged primate kidney graft survival (242, 196, 184, 181 and 148 days) compared to treatment with belatacept or ΑOX40L alone (8, 12 and 47 days vs. 7 days, respectively). Biopsy histology confirmed that combined belatacept+ΑOX40L suppresses the infiltration of primate kidney allografts by alloreactive T cells. Longitudinal flow cytometry of primate allograft recipient blood demonstrated that combined blockade did not deplete either B, CD4⁺ T or CD8⁺ T cells. Finally, serial monitoring of CMV viral loads in transplant recipients treated with combined blockade did not demonstrate any evidence of CMV reactivation, suggesting that this regimen does not severely compromise protective immunity.

Conclusions: These findings may have significant translational potential for future studies aimed at developing steroid and calcineurin inhibitor-sparing transplant immunosuppression regimens based on belatacept, and may also offer a strategy to improve upon the acute rejection rates associated with belatacept.

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