Belatacept is a high affinity version of the fusion protein CTLA4-Ig that blocks CD28 mediated T cell costimulation, providing a more targeted/less toxic form of immunosuppression. Patients treated with belatacept enjoy superior renal function, fewer cardiovascular and metabolic comorbidities, but experience higher rates and grades of acute rejection. We investigated mechanisms of acute rejection on belatacept based therapy in a non-human primate model of kidney transplantation. We performed 31 kidney transplants in fully MHC mismatched rhesus monkeys. Animals received belatacept or a calcineurin inhibitor, tacrolimus, in addition to steroids and cell cycle inhibitors to recapitulate clinically relevant immunosuppression strategy. Animals received therapy for 140 days. Median survival times were not significantly different between tacrolimus (MST=183) or belatacept (MST=179) treated animals. Six of sixteen belatacept treated animals rejected ("rejectors"), during the administration of therapy. Rejectors demonstrate higher frequency of CD8+ central memory T cells prior to transplantation. Furthermore, rejectors exhibit a unique signature of terminally differentiated CD45RA+CCR7- CD28lo, memory CD8 T cell allograft infiltrate, with a high expression of adhesion molecules VLA-4 and CD11a at the time of rejection. Animals who rejected after the cessation of belatacept therapy (“non-rejectors”) exhibited CD28hi, CD8 T cell infiltrate within the rejected allograft. Animals treated with tacrolimus did not exhibit a consistent phenotype in CD8 T cell infiltrate within the rejected allograft. In the weeks preceding rejection, circulating CD8 and CD4 T cells increased expression of adhesion molecules, such as VLA-4 and CD11a. We conclude that CD8 T cell memory poses a significant barrier to belatacept based immunosuppression strategies, and that costimulation independent acute rejection is mediated by terminally differentiated CD8 T cells. We propose that adjuvant therapies that target VLA-4 and CD11a may increase the efficacy of belatacept in kidney transplantation.

CITATION INFORMATION: Mathews D, Wakwe W, Lowe M, Breeden C, Leopardi F, Farris A, Song M, Strobert E, Jenkins J, Larsen C, Townsend R, Adams A. Acute Rejection in Non-Human Primates Treated with Belatacept Is Mediated by a Unique CD8 Memory Subset. Am J Transplant. 2016;16 (suppl 3).

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