Belatacept and Sirolimus Prolong Nonhuman Primate Renal Allograft Survival without a Requirement for Memory T Cell Depletion

• Type of Material: Article
• Authors: Denise Jennifer Lo, Emory University; Douglas J Anderson, Emory University; Timothy A Weaver, Emory University; Frank Leopardi, Emory University; Mingqing Song, Emory University; Alton B Farris III, Emory University; Elizabeth Strobert, Emory University; Joe Jenkins, Emory University; Nicole Turgeon, Emory University; Aneesh K Mehta, Emory University; Christian P Larsen, Emory University; Allan D Kirk, Emory University
• Language: English
• Date: 2013-02
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2012.04342.x/abstract
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 13
• Issue: 2
• Start Page: 320
• End Page: 328
• Grant/Funding Information: This study was funded by support from the NIH (5 U01 AI079223), Yerkes National Primate Research Center (P51RR-00065) and the Georgia Research Alliance.
• Keywords: alefacept; costimulation blockade; belatacept
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Belatacept is an inhibitor of CD28/B7 costimulation that is clinically indicated as a calcineurin inhibitor (CNI) alternative in combination with mycophenolate mofetil and steroids after renal transplantation. We sought to develop a clinically translatable, non-lymphocyte depleting, belatacept-based regimen that could obviate the need for both CNIs and steroids. Thus, based on murine data showing synergy between costimulation blockade and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched renal allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on costimulation blockade-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Belatacept and sirolimus therapy successfully prevented rejection in all animals. Tolerance was not induced, as animals rejected after withdrawal of therapy. The regimen did not deplete T cells. Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen, despite causing an intended depletion of memory T cells, and caused a marked reduction in regulatory T cells. Furthermore, alefacept treated animals had a significantly increased incidence of CMV reactivation, suggesting that this combination overly compromised protective immunity. These data support belatacept and sirolimus as a clinically translatable, non-depleting, CNI-free, steroid-sparing immunomodulatory regimen that promotes sustained rejection-free allograft survival after renal transplantation.