Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution1–3. Despite gene editing, the immune reactions following xenotransplantation can still cause transplant failure4. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host’s blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer cells and dendritic cells increased between postoperative day (POD) 10 and 28, concordant with an expansion of IgG and IgA B cell clonotypes and subsequent biopsy-confirmed antibody-mediated rejection (AMR) at POD33. Human T cell frequencies increased from POD14 and peaked between POD33 and POD49 in the blood and xenograft, which coincided with T cell receptor diversification, expansion of a restricted TRBV2 and TRBJ1 clonotype and histological evidence of combined AMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, which aligned with interferon-γ-driven inflammation and a T helper 1-type immune response. There was also evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury marked by S100A6 (ref. 5), SPP1 (also known as osteopontin)6 and COLEC11 (ref. 7) expression at POD21–POD33. Proteomic profiling revealed activation of human and pig complement, with a decreased human component after AMR therapy, in which complement was inhibited. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney and reveal potential immunomodulatory targets for improving xenograft survival.
