Swine Leukocyte Antigen DR Deletion is a Viable Option for Donor Pigs Used in Renal Xenotransplantation

OBJECTIVE: Swine Leukocyte Antigen-DR knockout (SLA-DR KO) pigs were created and evaluated for safety/infectious profile and the ability to function in a preclinical model of xenotransplantation. BACKGROUND: SLA-DR is the dominant class II MHC antigen in pigs. It is unclear whether it is feasible/safe to delete SLA-DR in donor pigs to be used in kidney xenotransplantation. METHODS: SLA DR KO pigs were created on the α-gal Sd a (GGTA1/B4GALNT2) deficient genetic background using CRISPR/Cas and somatic cell nuclear transfer. Pigs were evaluated for 55 potential zoonotic pathogens using digital droplet PCR assays. Four GGTA1/B4GALNT2/SLA-DR KO pig kidneys were transplanted into immunosuppressed rhesus monkeys. Renal function was monitored to evaluate whether these prototype kidneys could provide life-supporting renal function in a preclinical model. RESULTS: SLA-DR KO pigs were produced and are healthy more than 16 months later, devoid of 55 pathogens with zoonotic infectious potential. Recipients survived 7, 126, >365, and >365 days. Serum creatinine was maintained in long-term survivors (Cr 0.8 mg/dL in both). Early graft losses (7 and 126 d) occurred because of donor-specific pretransplant SLA antibodies detected using a SLA bead crossmatch assay. CONCLUSIONS: SLA-DR KO pigs are viable and safe to consider as potential donors in clinical trials. The SLA DR KO pig kidneys provided good long-term graft function in a preclinical model if the donor was not sensitized to other SLA antigens present in the donor pig. The SLA-DR KO prototype is promising for evaluation in pig-to-human clinical xenograft trials.