Abstract
The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T-cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the role of alloreactive memory T cells in mediating this resistance. To study the mechanisms of costimulatory blockade-resistant rejection and enhance the clinical efficacy of costimulatory blockade, we developed an experimental transplant system that models a donor-specific memory CD8(+) T-cell response. After confirming that graft-specific memory T cells mediate costimulatory blockade-resistant rejection, we characterized the role of integrins in this rejection. The resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1. Mechanistic studies revealed that in the presence of costimulatory blockade, anti-VLA-4 impaired T-cell trafficking to the graft but not memory T-cell recall effector function, whereas anti-LFA-1 attenuated both trafficking and memory recall effector function. As antagonists against these integrins are clinically approved, these findings may have significant translational potential for future clinical transplant trials.