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Inhibition of polymorphonuclear cells averts cytotoxicity against hypoimmune cells in xenotransplantation

Author

Listed:
  • Xiaomeng Hu

    (University of California San Francisco
    Sana Biotechnology Inc.)

  • Grigol Tediashvili

    (University of California San Francisco)

  • Alessia Gravina

    (University of California San Francisco)

  • Jonathan Stoddard

    (Oregon Health & Science University)

  • Trevor J. McGill

    (Oregon Health & Science University)

  • Andrew J. Connolly

    (University of California San Francisco)

  • Tobias Deuse

    (University of California San Francisco)

  • Sonja Schrepfer

    (University of California San Francisco
    Sana Biotechnology Inc.
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

Abstract

Allogeneic, immune-evasive hypoimmune (HIP) cell therapeutics that are HLA-depleted and overexpress CD47 create the opportunity to treat immunocompetent patients with cancer, degenerative, or autoimmune diseases. However, HIP cell therapy has not yet been established for xenotransplantation. Here we engineer, for human-to-non-human primate studies, human HIP* endothelial cells (EC) that are HLA-depleted and express macaque CD47 to allow compatibility with the macaque SIRPα immune checkpoint. Although no T cell, NK cell, or macrophage responses and no antibody-dependent cytotoxicity is observed in cynomolgus recipients, we reveal that macaque polymorphonuclear cells (PMN) show strong xenogeneic cytotoxicity against HIP* ECs. Inhibition of PMN killing using a multi-drug regimen leads to improved xenogeneic human HIP* EC survival in cynomolgus monkeys. Similarly, human PMNs show xenoreactivity against pig ECs, which has implications for clinical xenotransplantation. Accordingly, our engineered pig HIP* ECs that are SLA-depleted, overexpress human CD47, and additionally overexpress the PMN-inhibitory ligands CD99 and CD200, are protected against all human adaptive and innate cytotoxicity, including PMNs. In summary, specific targeting of PMN-mediated killing of the transplanted cells might improve outcomes for clinical pig-to-human xenotransplantation.

Suggested Citation

  • Xiaomeng Hu & Grigol Tediashvili & Alessia Gravina & Jonathan Stoddard & Trevor J. McGill & Andrew J. Connolly & Tobias Deuse & Sonja Schrepfer, 2025. "Inhibition of polymorphonuclear cells averts cytotoxicity against hypoimmune cells in xenotransplantation," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58774-7
    DOI: 10.1038/s41467-025-58774-7
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    References listed on IDEAS

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    1. Ranjith P. Anand & Jacob V. Layer & David Heja & Takayuki Hirose & Grace Lassiter & Daniel J. Firl & Violette B. Paragas & Adam Akkad & Sagar Chhangawala & Robert B. Colvin & Russell J. Ernst & Nichol, 2023. "Design and testing of a humanized porcine donor for xenotransplantation," Nature, Nature, vol. 622(7982), pages 393-401, October.
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