Multi-omics analysis of a pig-to-human decedent kidney xenotransplant.
Abstract
Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution<sup>1-3</sup>. Despite gene editing, the immune reactions following xenotransplantation can still cause transplant failure<sup>4</sup>. 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<sup>+</sup> 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. <sup>5</sup>), SPP1 (also known as osteopontin)<sup>6</sup> and COLEC11 (ref. <sup>7</sup>) 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.
EDRN PI Authors
- (None specified)
Medline Author List
- Al-Ali RA
- Albay J
- Aljabban I
- Andrijevic D
- Argibay D
- Ayares D
- Bartlett AQ
- Batzoglou S
- Bhatt R
- Boeke JD
- Bombardi R
- Camellato BR
- Chang A
- Chen HM
- Chong AS
- Crawford A
- Dowdell AK
- Eitan T
- Fairchild RL
- Ferdosi S
- Gandla D
- Gao H
- Gao S
- Gragert L
- Griesemer A
- Guo Q
- Habara AH
- Hamilton L
- Heguy A
- Herati RS
- Holmes MV
- Jaffe I
- Kagermazova L
- Kaikkonen MU
- Keating BJ
- Kellis M
- Khalil K
- Kim J
- Lau B
- Linna-Kuosmanen S
- Lorber M
- Loupy A
- Maden B
- Mangiola M
- Mattoo A
- Mauduit V
- Mohebnasab M
- Moi K
- Montgomery RA
- Motter JD
- Nellore A
- O'Brien DP
- Piening BD
- Robinson FL
- Rophina M
- Saxena D
- Schmauch E
- Siddiqui A
- Skolnik EY
- Snyder MP
- Stern J
- Stukalov A
- Taft R
- Tatapudi VS
- Thomas SC
- Vikman S
- Wang C
- Weldon E
- Williams SH
- Wu L
- Zanoni F
- Zayas Z
- Zhang W