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Late Renal Xenograft Failure Is Antibody-Mediated: Description of the Longest-Reported Survival in Pig-to-Primate Renal Xenotransplantation.

L. Higginbotham,1 S. Kim,1 D. Mathews,1 A. Stephenson,1 C. Breeden,1 C. Larsen,1 M. Ford,1 K. Newell,1 A. Tector,2 A. Adams.1

1Emory Transplant Center, Emory University Hospital, Atlanta, GA
2Indiana University School of Medicine, Indianapolis, IN.

Meeting: 2016 American Transplant Congress

Abstract number: A6

Keywords: Kidney transplantation, Primates, Xenotransplantation

Session Information

Date: Saturday, June 11, 2016

Session Name: Poster Session A: B cells & AMR, Alloreactivity, Immune Regulation & Regulatory T Cells, T Cell Biology and Alloreactivity, Immunesuppression

Session Time: 5:30pm-7:30pm

 Presentation Time: 5:30pm-7:30pm

Location: Halls C&D

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Introduction. Xenotransplantation has the potential to alleviate the organ supply shortage, yet pig-to-primate renal xenotransplant has met limited success due to natural preformed anti-pig antibody. Genetically altered pigs lacking expression of xenoantigens, most notably galactose-α1,3-galactose (Gal), have improved outcomes but median survival times remain low. We report long-term survival in pig-to-primate renal transplant using Gal knockout/CD55 transgenic pigs. Methods. Serum samples from Rhesus macaque transplant candidates were incubated with pig GGTA1KO PBMC and stained with anti-human IgM and IgG to measure preformed anti-pig antibody titers. Four primates with the lowest preformed IgG titers and one macaque with the highest were selected for transplantation. Animals underwent bilateral nephrectomy then life-sustaining renal transplant from donor transgenic GGTA1KO/hDAF pigs. Animals were treated with T cell depletion (anti-CD4 and anti-CD8) plus costimulation blockade with either anti-CD154 (n=3) or belatacept (n=2) plus daily MMF/steroids. Post-transplant renal biopsies were submitted for H&E, trichrome, PAS, and Von Kossa staining. Serum creatinine>5mg/dL or BUN>100mg/dL on two consecutive measurements defined clinical rejection. Results. Animals with low anti-pig antibody titers survived longer than the high-titer monkey (MST=90.5 days [n=4]; vs MST=6 days [n=1]; p<0.05). Within the low-titer group, anti-CD154 costimulation blockade prolonged survival more than belatacept (MST=235 days [160 and 310 days, n=2] vs MST=17.5 days [14 and 21 days, n=2]). At rejection, xenografts of long-term survivors showed evidence of AMR with IgG deposition and positive C4d staining. Electron microscopy revealed glomerulopathy in both xenografts, and one long-term survivor developed significant proteinuria. Conclusions. Pre-transplant antibody screening and costimulation blockade promote renal xenograft survival in a pig-to-macaque kidney transplant model. This description of the longest-reported survival, 160 & 310 days, offers important insight into late renal xenograft rejection. Late failure is antibody-mediated and associated with proteinuria. Deletion of additional non-Gal antigens is likely important for avoidance of late AMR.

CITATION INFORMATION: Higginbotham L, Kim S, Mathews D, Stephenson A, Breeden C, Larsen C, Ford M, Newell K, Tector A, Adams A. Late Renal Xenograft Failure Is Antibody-Mediated: Description of the Longest-Reported Survival in Pig-to-Primate Renal Xenotransplantation. Am J Transplant. 2016;16 (suppl 3).

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To cite this abstract in AMA style:

Higginbotham L, Kim S, Mathews D, Stephenson A, Breeden C, Larsen C, Ford M, Newell K, Tector A, Adams A. Late Renal Xenograft Failure Is Antibody-Mediated: Description of the Longest-Reported Survival in Pig-to-Primate Renal Xenotransplantation. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/late-renal-xenograft-failure-is-antibody-mediated-description-of-the-longest-reported-survival-in-pig-to-primate-renal-xenotransplantation/. Accessed April 16, 2021.

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