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

Publication Title

Nature

Authors

Eloi Schmauch
Brian D. Piening, Earle A. Chiles Research Institute, Providence Health, Portland, OR, USA.; Providence Institute for Clinical Innovation, Providence Health, Portland, OR, USA.Follow
Alexa K Dowdell, Earle A. Chiles Research Institute, Providence Health, Portland, OR, USA.; Providence Institute for Clinical Innovation, Providence Health, Portland, OR, USA.Follow
Maedeh Mohebnasab
Simon H Williams
Alexey Stukalov
Fred L Robinson, Earle A. Chiles Research Institute, Providence Health, Portland, OR, USA.Follow
Robin Bombardi
Ian Jaffe
Karen Khalil
Jacqueline Kim
Imad Aljabban
Tal Eitan
Darragh P O'Brien
Mercy Rophina
Chan Wang
Alexandra Q Bartlett, Earle A. Chiles Research Institute, Providence Health, Portland, OR, USA.Follow
Francesca Zanoni
Jon Albay
David Andrijevic
Berk Maden
Vincent Mauduit
Susanna Vikman
Diana Argibay
Zasha Zayas
Leah Wu
Kiana Moi
Billy Lau
Weimin Zhang
Loren Gragert
Elaina Weldon
Hui Gao
Lauren Hamilton, Earle A. Chiles Research Institute, Providence Health, Portland, OR, USA.Follow
Larisa Kagermazova
Brendan R Camellato
Divya Gandla
Riyana Bhatt
Sarah Gao
Rudaynah A Al-Ali
Alawi H Habara
Andrew Chang
Shadi Ferdosi
Han M Chen
Jennifer D Motter
Fiorella A Chacon
Scott C Thomas
Deepak Saxena
Robert L Fairchild
Alexandre Loupy
Adriana Heguy
Ali Crawford
Serafim Batzoglou
Michael P Snyder
Asim Siddiqui
Michael V Holmes
Anita S Chong
Minna U Kaikkonen
Suvi Linna-Kuosmanen
David Ayares
Marc Lorber
Anoma Nellore
Edward Y Skolnik
Aprajita Mattoo
Vasishta S Tatapudi
Ryan Taft
Massimo Mangiola
Qian Guo
Ramin S Herati
Jeffrey Stern
Adam Griesemer
Manolis Kellis
Jef D Boeke
Robert A Montgomery
Brendan J Keating

Document Type

Article

Publication Date

11-13-2025

Keywords

oregon; portland

Abstract

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 (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A65, SPP16 (Osteopontin), and COLEC117, at POD21-POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

Area of Special Interest

Kidney & Diabetes

Specialty/Research Institute

Nephrology

DOI

10.1038/s41586-025-09846-7