• Alexandre Loupy, Valentin Goutaudier, Alessia Giarraputo, Fariza Mezine, Erwan Morgand, Blaise Robin, Karen Khalil, Sapna Mehta, Brendan Keating, Amy Dandro, Anaïs Certain, Pierre-Louis Tharaux, Navneet Narula, Renaud Tissier, Sébastien Giraud, Thierry Hauet, Harvey I Pass, Aurélie Sannier, Ming Wu, Adam Griesemer, David Ayares, Vasishta Tatapudi, Jeffrey Stern, Carmen Lefaucheur, Patrick Bruneval, Massimo Mangiola, and Robert A Montgomery.
• Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. Electronic address: alexandre.loupy@inserm.fr.
• Lancet. 2023 Sep 30; 402 (10408): 115811691158-1169.

BackgroundCross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach.MethodsWe did a complete phenotyping of two pig kidney xenografts transplanted to decedent humans. We used a multimodal strategy combining morphological evaluation, immunophenotyping (IgM, IgG, C4d, CD68, CD15, NKp46, CD3, CD20, and von Willebrand factor), gene expression profiling, and whole-transcriptome digital spatial profiling and cell deconvolution. Xenografts before implantation, wild-type pig kidney autografts, as well as wild-type, non-transplanted pig kidneys with and without ischaemia-reperfusion were used as controls.FindingsThe data collected from xenografts suggested early signs of antibody-mediated rejection, characterised by microvascular inflammation with immune deposits, endothelial cell activation, and positive xenoreactive crossmatches. Capillary inflammation was mainly composed of intravascular CD68+ and CD15+ innate immune cells, as well as NKp46+ cells. Both xenografts showed increased expression of genes biologically related to a humoral response, including monocyte and macrophage activation, natural killer cell burden, endothelial activation, complement activation, and T-cell development. Whole-transcriptome digital spatial profiling showed that antibody-mediated injury was mainly located in the glomeruli of the xenografts, with significant enrichment of transcripts associated with monocytes, macrophages, neutrophils, and natural killer cells. This phenotype was not observed in control pig kidney autografts or in ischaemia-reperfusion models.InterpretationDespite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results.FundingOrganX and MSD Avenir.Copyright © 2023 Elsevier Ltd. All rights reserved.

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