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Publications

Journal Article Case Reports Ppublish

PubMed: 42199164 DOI: 10.1111/xen.70143

Noninvasive Monitoring of Complement Using the Bioluminescent Modified Ham Assay in the Second Porcine-to-Human Live Heart Transplant.

Xenotransplantation 33(3):e70143

Authors: Michael A Cole, Andy Tully, Javier Galindo, Avneesh K Singh, Meryl Waldman, Janhavi Athale, Idris Boudhabhay, Erwan Morgand, Fariza Mezine, Valentin Goutaudier, Aurélie Sannier, Brad Lewis, Jamey Kain, Mike Ero, Lubka Roumenina, Patrick Bruneval, Robert Christenson, Lo Tamburro, Alan Burke, Cinthia Drachenburg, Alexandre Loupy, David Ayares, Robert A Brodsky, Bartley P Griffith, Muhammad M Mohiuddin, Alison Grazioli

Affiliations

  • Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
  • Cardiothoracic Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Clinical Nephrology Section, NIDDK, National Institutes of Health Clinical Research Center, Bethesda, Maryland, USA.
  • Department of Medicine, University of Maryland School of Medicine, Program in Trauma, Baltimore, Maryland, USA.
  • Centre de Recherche des Cordeliers, Institut National de La SantĂ© Et De La Recherche MĂ©dicale, Sorbonne UniversitĂ©, UniversitĂ© De Paris CitĂ©, Inflammation, Complement and Cancer Team, FHU COMET, Paris, France.
  • Paris Institute for Transplantation and Organ Regeneration, INSERM U970, UniversitĂ© Paris CitĂ©, Paris, France.
  • Clinical Investigation Center CIC-1418, DMU CARTE, Georges Pompidou European Hospital, Assistance Publique - HĂ´pitaux de Paris, Paris, France.
  • Machaon Diagnostics, Berkeley, California, USA.
  • Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • Revivicor Inc. Blacksburg, Virginia, USA.

Abstract

Complement activation is a major barrier to xenotransplantation. We report detailed complement monitoring in a 58-year-old man who received a 10 gene-edited porcine heart expressing human complement regulators CD46 and CD55. Despite these transgenes and prophylactic systemic complement inhibition with C1 esterase inhibitor (C1INH), early surveillance biopsy on post-operative day (POD) 13 showed significant histologic evidence of complement deposition with C3d and C4d within capillaries and endothelial activation. In light of these findings, treatment was escalated to terminal complement inhibition using eculizumab. Post-operative complement activity was assessed via immunohistochemistry and dynamic ex vivo serum assays, including a novel bioluminescent modified Ham (bmHam) assay. Following eculizumab initiation, serum sC5b-9 dropped to undetectable levels, and bmHam cytotoxicity decreased significantly, confirming terminal pathway inhibition. Dilutional bmHam assays further demonstrated stronger complement blockade with eculizumab than with C1INH. However, repeat transplant biopsy on POD 30 biopsy showed persistence of anti-C4d+ and anti-C3c+ staining, and increased C5b-9 compared to POD13. This breakthrough was identified by the dilutional bmHam but was not detected by changes in CH50 or sC5b-9. These findings highlight the potential need for early terminal complement inhibition and integrated functional monitoring as critical components of xenotransplant management.

MeSH

Graft Rejection, Genes, Transplantation, Heterologous, Serum, Heart, Biopsy, Heart Transplantation, Transplants, Complement System Proteins, Monitoring, Immunologic