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

ABSTRACT

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.