Knock-out of N-glycolylneuraminic acid attenuates antibody-mediated rejection in xenogenically perfused porcine lungs
- Authors
- Chaban, Ryan; Habibabady, Zahra; Hassanein, Wessam; Connolly, Margaret R.; Burdorf, Lars; Redding, Emily; Laird, Christopher; Ranek, Jolene; Braileanu, Gheorghe; Sendil, Selin; Cheng, Xiangfei; Sun, Wenji; O'Neill, Natalie A.; Kuravi, Kasinath; Hurh, Sunghoon; Ayares, David L.; Azimzadeh, Agnes M.; Pierson, Richard N., III
- Issue Date
- Nov-2022
- Publisher
- Blackwell Publishing Inc.
- Keywords
- lung transplantation; Neu5Gc; swine; xenotransplantation
- Citation
- Xenotransplantation, v.29, no.6
- Indexed
- SCIE
SCOPUS
- Journal Title
- Xenotransplantation
- Volume
- 29
- Number
- 6
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/61696
- DOI
- 10.1111/xen.12784
- ISSN
- 0908-665X
1399-3089
- Abstract
- Background
Antibody-mediated rejection has long been known to be one of the major organ failure mechanisms in xenotransplantation. In addition to the porcine α1,3-galactose (α1,3Gal) epitope, N-Glycolylneuraminic acid (Neu5Gc), a sialic acid, has been identified as an important porcine antigen against which most humans have pre-formed antibodies. Here we evaluate GalTKO.hCD46 lungs with an additional cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) gene knock-out (Neu5GcKO) in a xenogeneic ex vivo perfusion model
Methods
Eleven GalTKO.hCD46.Neu5GcKO pig lungs were perfused for up to 6 h with fresh heparinized human blood. Six of them were treated with histamine (H) blocker famotidine and 1-thromboxane synthase inhibitor Benzylimidazole (BIA) and five were left untreated. GalTKO.hCD46 lungs without Neu5GcKO (n = 18: eight untreated and 10 BIA+H treated) served as a reference. Functional parameters, blood, and tissue samples were collected at pre-defined time points throughout the perfusion
Results
All but one Neu5GcKO organs maintained adequate blood oxygenation and “survived” until elective termination at 6 h whereas two reference lungs failed before elective termination at 4 h. Human anti-Neu5Gc antibody serum levels decreased during the perfusion of GalTKO.hCD46 lungs by flow cytometry (∼40% IgM, 60% IgG), whereas antibody levels in Neu5GcKO lung perfusions did not fall (IgM p = .007; IgG p < .001). Thromboxane elaboration, thrombin generation, and histamine levels were significantly reduced with Neu5GcKO lungs compared to reference in the untreated groups (p = .007, .005, and .037, respectively); treatment with BIA+H masked these changes. Activation of platelets, measured as CD62P expression on circulating platelets, was lower in Neu5GcKO experiments compared to reference lungs (p = .023), whereas complement activation (as C3a rise in plasma) was not altered. MCP-1 and lactotransferin level elevations were blunted in Neu5GcKO lung perfusions (p = .007 and .032, respectively). Pulmonary vascular resistance (PVR) rise was significantly attenuated and delayed in untreated GalTKO.hCD46.Neu5GcKO lungs in comparison to the untreated GalTKO.hCD46 lungs (p = .003)
Conclusion
Additional Neu5GcKO in GalTKO.hCD46 lungs significantly reduces parameters associated with antibody-mediated inflammation and activation of the coagulation cascade. Knock-out of the Neu5Gc sialic acid should be beneficial to reduce innate immune antigenicity of porcine lungs in future human recipients.
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Collections - 4. Research institute > Institute of Human Behavior and Genetics > 1. Journal Articles
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