Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection

• Type of Material: Article
• Authors: Douglas Anderson, Emory University; Denise Lo, Emory University; F. Leopardi, Duke University; Mingqing Song, Duke University; Nicole Turgeon, Emory University; Elizabeth Strobert, Emory University; Joe Jenkins, Emory University; Rijian Wang, University of Massachusetts; Keith A. Reimann, University of Massachusetts; Christian Larsen, Emory University; Allan Kirk, Emory University
• Language: English
• Date: 2016-05-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
• Final Published Version (URL): http://dx.doi.org/10.1111/ajt.13628
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 16
• Issue: 5
• Start Page: 1456
• End Page: 1464
• Grant/Funding Information: Anti-LFA-1 antibodies were provided through the NHP Reagent Resource supported by NIAID contract HHSN272201300031C.; Further grant support of the Yerkes National Primate Research Center was provided by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132.; Funding for this research was provided by a grant from the NIH, 1U01AI079223, U01AI084150 and 2U19AI051731-11.; Dr. Anderson was partially supported by the ASTS-Genentech Scientist Scholarship.
• Keywords: T-CELLS; EXPRESSION; LYMPHOCYTES; CYCLOSPORINE; Science & Technology; ALLOGRAFT-REJECTION; BELATACEPT; ADHESION; Life Sciences & Biomedicine; PHASE-III; Surgery; LFA-1; Transplantation; EFALIZUMAB
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology

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.