Xenoantigen deletion and chemical immunosuppression can prolong renal xenograft survival

Andrew B. Adams, Steven C. Kim, Gregory R. Martens, Joseph M. Ladowski, Jose L. Estrada, Luz M. Reyes, Cindy Breeden, Allison Stephenson, Devin E. Eckhoff, Matt Tector, Alfred Joseph Tector

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Objective: Xenotransplantation using pig organs could end the donor organ shortage for transplantation, but humans have xenoreactive antibodies that cause early graft rejection. Genome editing can eliminate xenoantigens in donor pigs to minimize the impact of these xenoantibodies. Here we determine whether an improved cross-match and chemical immunosuppression could result in prolonged kidney xenograft survival in a pig-to-rhesus preclinical model. Methods: Double xenoantigen (Gal and Sda) knockout (DKO) pigs were created using CRISPR/Cas. Serum from rhesus monkeys (n ¼ 43) was cross-matched with cells from the DKO pigs. Kidneys from the DKO pigs were transplanted into rhesus monkeys (n ¼ 6) that had the least reactive cross-matches. The rhesus recipients were immunosuppressed with anti-CD4 and anti-CD8 T-cell depletion, anti-CD154, mycophenolic acid, and steroids. Results: Rhesus antibody binding to DKO cells is reduced, but all still have positive CDC and flow cross-match. Three grafts were rejected early at 5, 6, and 6 days. Longer survival was achieved in recipients with survival to 35, 100, and 435 days. Each of the 3 early graft losses was secondary to IgM antibody-mediated rejection. The 435-day graft loss occurred secondary to IgG antibody-mediated rejection. Conclusions: Reducing xenoantigens in donor pigs and chemical immunosuppression can be used to achieve prolonged renal xenograft survival in a preclinical model, suggesting that if a negative cross-match can be obtained for humans then prolonged survival could be achieved.

Original languageEnglish (US)
Pages (from-to)564-573
Number of pages10
JournalAnnals of surgery
Volume268
Issue number4
DOIs
StatePublished - 2018
Externally publishedYes

Bibliographical note

Funding Information:
From the *Emory School of Medicine, Atlanta, GA; and †University of Alabama Birmingham, Birmingham, AL. Funding: This work was funded by grants from the National Institutes of Health (1R01AI26322) and ORIP/OD P51OD011132 and portions were funded by the Indiana University Health Transplant Institute. Conflicts of interest: DEE and AJT have had funding from United Therapeutics. AJT has applied for and been awarded patents related to genetic engineering of pigs for use in xenotransplantation. AJT has also founded XenoBridge llc. Other authors do not claim conflicts. Reprints: Alfred Joseph Tector, MD, PhD, ZRB 701, 1720 2nd Ave South Birmingham, AL 35294. E-mail: jtector@uab.edu. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0003-4932/18/26804-0564 DOI: 10.1097/SLA.0000000000002977

Publisher Copyright:
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Keywords

  • Antigen
  • Kidney
  • Knockout
  • Primate
  • Xenotransplantation

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