Background: MHCs play essential roles in allogeneic and xenogeneic rejection. In this study, we generated SLA-deficient pigs to mitigate primate anti-pig immune responses.
Methods: SLA-deficient pigs (GBC-4F) were produced by deleting three pig genes (GGTA1, B2M, and CIITA) and expressing four human genes (hCD55, hCD46, hEPCR, and hTFPI). Gene editions were confirmed by flow cytometry and confocal microscopy. Pig artery tissue (PAT) and kidney were transplanted into human immune system (HIS) mice and rhesus monkeys (conditioned with or without anti-CD154 antibody) respectively, to evaluate anti-pig xenogeneic immune responses.
Results: The GBC-4F pigs exhibited deficiency of α-Gal, SLA-I, SLA-II, along with widespread expression of hCD55 and hCD46 and low expression of hEPCR and hTFPI. In the PAT transplantation model, GBC-4F PAT grafts were clearly detectable five weeks post-transplantation, whereas the wild-type grafts were rejected by three weeks. Human T cells from HIS mice grafted with GBC-4F PAT showed significantly reduced anti-pig responses compared to those from wild-type PAT-grafted HIS mice. In the kidney transplantation model, two monkeys without anti-CD154 antibody survived for 17 and 19 days, showing clear evidence of immune rejection. However, two monkeys treated with anti-CD154 antibody survived 51 and 70 days, with deaths likely due to complications such as pneumonia, renal hydronephrosis, and ureteral obstruction.
Conclusion: These findings suggest that SLA deficiency significantly reduces human anti-pig immune rejection in vivo, and anti-CD154 antibody treatment enhances SLA deficient pig kidney survival in monkeys, highlighting the importance of postoperative care for the long-term survival of xenografts.