Xenoantigen Deletion and Chemical Immunosuppression Can Prolong Renal Xenograft Survival
Andrew B. Adams*1, Steven C. Kim*1, Gregory R Martens*2, Joseph M. Ladowski*2, Jose L. Estrada*2, Luz M. Reyes*2, Cindy Breeden*1, Allison Stephenson*1, Devin E. Eckhoff2, Matt Tector*2, Alfred J. Tector2
1Emory School of Medicine, Atlanta, GA;2University of Alabama Birmingham, Birmingham, AL
OBJECTIVE(S): 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 crossmatch 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=30) was cross matched with cells from the DKO pigs. Kidneys from the DKO pigs were transplanted into rhesus monkeys (n=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: Each of the rhesus had a positive CDC crossmatch. Three grafts were rejected early at 5, 6, and 6 days. Two recipients are alive at >35 days, and one graft was rejected at 435 days. Each of the three 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 crossmatch can be obtained for humans that prolonged survival could be achieved.
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