Multi-omics analysis of a pig-to-human decedent kidney xenotransplant

Journal article

Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution^1,2,3. 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.

Authors: Schmauch, E; Piening, BD; Dowdell, AK; Mohebnasab, M; Williams, SH

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature
• Volume: 650
• Issue: 8100
• Pages: 205-217
• Publication date: 2025-11-13
• Acceptance date: 2025-11-03
• DOI: 10.1038/s41586-025-09846-7
• EISSN: 1476-4687
• ISSN: 0028-0836
• Pmid: 41233547
• Language: English
• Keywords: inflammatory and immune system; organ transplantation; kidney disease; biotechnology; transplantation; immunotherapy