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Author Notes:

Corresponding Author: Allan D. Kirk, MD, PhD, Box 3704, Duke University Medical Center, Durham, NC 27710, Allan.kirk@duke.edu

"This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."

The authors would like to thank the research support staff of the Emory Transplant Center and the veterinary staff at the Yerkes National Primate Research Center for their efforts on our behalf.

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation.

Dr. Larsen has received funding from Bristol-Myers-Squibb for clinical trials and preclinical studies

The other authors have no conflicts of interest to disclose.

Subjects:

Research Funding:

Funding for this research was provided by a grant from the NIH, 1U01AI079223, U01AI084150 and 2U19AI051731-11.

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.

Anti-LFA-1 antibodies were provided through the NHP Reagent Resource supported by NIAID contract HHSN272201300031C.

Dr. Anderson was partially supported by the ASTS-Genentech Scientist Scholarship.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Surgery
  • Transplantation
  • T-CELLS
  • ALLOGRAFT-REJECTION
  • PHASE-III
  • EFALIZUMAB
  • BELATACEPT
  • ADHESION
  • LFA-1
  • CYCLOSPORINE
  • LYMPHOCYTES
  • EXPRESSION

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

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Journal Title:

American Journal of Transplantation

Volume:

Volume 16, Number 5

Publisher:

, Pages 1456-1464

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

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