Anti–Leukocyte Function‐Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade–Resistant Rejection. Issue 5 (14th January 2016)

• Record Type: Journal Article
• Authors: Anderson, D. J.; Lo, D. J.; Leopardi, F.; Song, M.; Turgeon, N. A.; Strobert, E. A.; Jenkins, J. B.; Wang, R.; Reimann, K. A.; Larsen, C. P.; Kirk, A. D.
• Is Part Of: American journal of transplantation. Volume 16:Issue 5(2016:May)
• Page Start: 1456
• Page End: 1464
• Publication Date: 2016-01-14
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.13628
• Languages: English
• ISSNs: 1600-6135

Abstract

Abstract : Costimulation blockade with the fusion protein belatacept provides a desirable side effect profile and improvement in renal function compared with calcineurin inhibition in renal transplantation. This comes at the cost of increased rates of early acute rejection. Blockade of the integrin molecule leukocyte function‐associated antigen 1 (LFA‐1) has been shown to be an effective adjuvant to costimulation blockade in a rigorous nonhuman primate (NHP) model of islet transplantation; therefore, we sought to test this combination in an NHP renal transplant model. Rhesus macaques received belatacept maintenance therapy with or without the addition of LFA‐1 blockade, which was achieved using a murine‐derived LFA‐1–specific antibody TS1/22. Additional experiments were performed using chimeric rhesus IgG1 (TS1/22R1) or IgG4 (TS1/22R4) variants, each engineered to limit antibody clearance. Despite evidence of proper binding to the target molecule and impaired cellular egress from the intravascular space indicative of a therapeutic effect similar to prior islet studies, LFA‐1 blockade failed to significantly prolong graft survival. Furthermore, evidence of impaired protective immunity against cytomegalovirus was observed. These data highlight the difficulties in translating treatment regimens between organ models and suggest that the primarily vascularized renal model is more robust with regard to belatacept‐resistant rejection than the islet model. Abstract : In a nonhuman primate model of renal transplantation, the addition of short‐term LFA‐1 blockade to belatacept maintenance therapy fails to prolong graft survival beyond belatacept alone, contrary to previous results in other models, and impairs protective immunity, suggesting limited clinical applicability of this approach.