Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study.

Autor:	Loupy A; 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., Goutaudier V; 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., Giarraputo A; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Cardiovascular Pathology and Pathological Anatomy, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy., Mezine F; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France., Morgand E; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France., Robin B; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France., Khalil K; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Pharmacy, NYU Langone Health, New York, NY, USA., Mehta S; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA., Keating B; Division of Transplantation, Department of Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA., Dandro A; Revivicor, Blacksburg, VA, USA., Certain A; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France., Tharaux PL; Paris Cardiovascular Research Center, PARCC, INSERM U970, Université Paris Cité, Paris, France., Narula N; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA., Tissier R; Ecole Nationale Vétérinaire d'Alfort, IMRB, After ROSC Network, Maisons-Alfort, France., Giraud S; INSERM U1313, IRMETIST, Université de Poitiers et CHU de Poitiers, Poitiers, France., Hauet T; INSERM U1313, IRMETIST, Université de Poitiers et CHU de Poitiers, Poitiers, France., Pass HI; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Cardiothoracic Surgery, NYU Grossman School of Medicine, New York, NY, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY, USA., Sannier A; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Pathology, Bichat Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France., Wu M; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA., Griesemer A; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY, USA., Ayares D; Revivicor, Blacksburg, VA, USA., Tatapudi V; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA., Stern J; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY, USA., Lefaucheur C; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France., Bruneval P; Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Pathology, Georges Pompidou European Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France., Mangiola M; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA., Montgomery RA; NYU Langone Transplant Institute, NYU Langone Health, New York, NY, USA; Department of Surgery, NYU Grossman School of Medicine, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2023 Sep 30; Vol. 402 (10408), pp. 1158-1169. Date of Electronic Publication: 2023 Aug 17.
DOI:	10.1016/S0140-6736(23)01349-1
Abstrakt:	Background: Cross-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. Methods: We 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. Findings: The 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. Interpretation: Despite 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. Funding: OrganX and MSD Avenir. Competing Interests: Declaration of interests AD and DA are employees of Revivicor. All other authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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