Antibody Responses Against Swine Leukocyte Antigens Contribute to Early Rejection After Pig-To-Monkey Kidney Xenotransplantation.

Swine leukocyte antigens (SLA) may be a new type of xenoantigen. Previous studies on SLA have primarily focused on their cross-reactivity with HLA. However, the role of SLA in stimulating xenogeneic immune responses after xenotransplantation remains unclear. In our recent kidney xenotransplantation study in rhesus monkeys using GTKO/hCD55 or GTKO/β4GalNT2KO/hCD55/hTBM pigs as donors, 5 of 13 recipients experienced early AMR accompanied by a marked increase in anti-donor pig antibodies. Flow cytometry analysis showed that the terminal sera of these recipients contained significant de novo anti-SLA antibodies, as evidenced by reduced antibody binding to GTKO/SLA-I/II KO pig PBMCs. Using GTKO/β4GalNT2KO pAECs with or without pIFN-γ stimulation as target cells, we found that the binding levels of the terminal sera to pAECs were positively correlated with SLA expression. IP-MS analysis identified multiple SLA class I and class II epitopes targeted by recipient IgG antibodies, with SLA-2 emerging as a dominant immunogenic antigen. In addition, xenogeneic MLR assays revealed that deletion of SLA, particularly SLA class II, markedly attenuated human anti-pig T-cell proliferation. These results demonstrate that induced anti-SLA antibodies can be generated in the early period after pig-to-monkey kidney xenotransplantation and may play a significant role in the development of AMR.