Inhibition of polymorphonuclear cells averts cytotoxicity against hypoimmune cells in xenotransplantation

Xiaomeng Hu, Grigol Tediashvili, Alessia Gravina, Jonathan Stoddard, Trevor J. McGill, Andrew J. Connolly, Tobias Deuse and Sonja Schrepfer ()
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Xiaomeng Hu: University of California San Francisco
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

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58774-7

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