Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model

• Type of Material: Article
• Authors: Laura Higginbotham, Emory University; Dave Mathews, Emory University; Cynthia Breeden, Emory University; Mingqing Song, Emory University; Alton Farris III, Emory University; Christian Larsen, Emory University; Mandy Ford, Emory University; Andrew J. Lutz, Indiana University; Matthew Tector, Indiana University; Kenneth Newell, Emory University; A. Joseph Tector, Indiana University; Andrew Adams, Emory University
• Language: English
• Date: 2015-05-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 John Wiley & Sons A/S.
• Final Published Version (URL): http://dx.doi.org/10.1111/xen.12166
• Title of Journal or Parent Work: Xenotransplantation
• ISSN: 0908-665X
• Volume: 22
• Issue: 3
• Start Page: 221
• End Page: 230
• Grant/Funding Information: This study was supported by research funding from the Emory Transplant Center and the Yerkes National Primate Research Center Base Grant RR00165.
• Keywords: BELATACEPT; non-human primate; Research & Experimental Medicine; renal transplantation; ENDOTHELIAL-CELLS; xenoantigen; transgenic pigs; ALLOGRAFT SURVIVAL; Life Sciences & Biomedicine; CYNOMOLGUS MONKEYS; alpha-1,3-galactosyltransferase; KNOCKOUT PIGS; xenotransplantation; Transplantation; NONHUMAN-PRIMATES; human decay-accelerating factor; Science & Technology; costimulation blockade; RENAL-ALLOGRAFT; GRAFT-SURVIVAL
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation.