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Evaluation of human and non‐human primate antibody binding to pig cells lacking GGTA 1/CMAH/β4Gal NT 2 genes
Abstract
Background: Simultaneous inactivation of pig GGTA 1 and CMAH genes eliminates carbohydrate xenoantigens recognized by human antibodies. The β4Gal NT 2 glycosyltransferase may also synthesize xenoantigens. To further characterize glycan‐based species incompatibilities, we examined human and non‐human primate antibody binding to cells derived from genetically modified pigs lacking these carbohydrate‐modifying genes. Methods: The Cas9 endonuclease and gRNA were used to create pigs lacking GGTA 1, GGTA 1/CMAH, or GGTA 1/CMAH/β4Gal NT 2 genes. Peripheral blood mononuclear cells were isolated from these animals and examined for binding to IgM and IgG from humans, rhesus macaques, and baboons. Results: Cells from GGTA 1/CMAH/β4Gal NT 2 deficient pigs exhibited reduced human IgM and IgG binding compared to cells lacking both GGTA 1 and CMAH. Non‐human primate antibody reactivity with cells from the various pigs exhibited a slightly different pattern of reactivity than that seen in humans. Simultaneous inactivation of the GGTA 1 and CMAH genes increased non‐human primate antibody binding compared to cells lacking either GGTA 1 only or to those deficient in GGTA 1/CMAH/β4Gal NT 2. Conclusions: Inactivation of the β4Gal NT 2 gene reduces human and non‐human primate antibody binding resulting in diminished porcine xenoantigenicity. The increased humoral immunity of non‐human primates toward GGTA 1‐/CMAH‐deficient cells compared to pigs lacking either GGTA 1 or GGTA 1/CMAH/β4Gal NT 2 highlights the complexities of carbohydrate xenoantigens and suggests potential limitations of the non‐human primate model for examining some genetic modifications. The progressive reduction of swine xenoantigens recognized by human immunoglobulin through inactivation of pig GGTA 1/CMAH/β4Gal NT 2 genes demonstrates that the antibody barrier to xenotransplantation can be minimized by genetic engineering.
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In vitro analysis suggests that a human-compatible porcine donor should ideally have all three glycans eliminated to match with the absence of the three glycans in humans.
“However, in vitro analysis suggests that a human-compatible porcine donor should ideally have all three glycans eliminated to match with the absence of the three glycans in humans8,9.”
From Design and testing of a humanized porcine donor for xenotransplantation (2023) · cites this paper as [9]
The Results report that deleting all three genes further reduced human antibody binding, supporting the in vitro rationale for a triple-knockout donor. But the Discussion says only approximately 5% of humans have inactive β4GalNT2; the paper does not support the claim that all three corresponding glycans are absent in humans. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA porcine donor carrying a CMAH knockout is thought not to survive in OWMs considering complication from a CMAH knockout.
“Although a porcine donor carrying a CMAH knockout is thought not to survive in OWMs considering complication from a CMAH knockout8,9, renal grafts derived from the 3KO.7TG ± RI porcine donor supported life long-term in cynomolgus monkeys, up to 758 days.”
From Design and testing of a humanized porcine donor for xenotransplantation (2023) · cites this paper as [9]
The Discussion (page not available) reports that deleting CMAH on a GGTA1-knockout background increased baboon and rhesus antibody binding, a potential complication for pig-to-primate transplantation. The paper measured antibody binding, not graft survival, and does not say that CMAH-knockout porcine grafts are unlikely to survive in Old World monkeys. (LLM, conf=0.86)
Experimental — accuracy not yet measured3KO porcine cells possess additional xenoantigens recognized by OWM serum.
“This is consistent with other reports that 3KO porcine cells possess additional xenoantigens recognized by OWM serum8,9.”
From Design and testing of a humanized porcine donor for xenotransplantation (2023) · cites this paper as [9]
CMAH inactivation may produce a novel antigen xenogenic to the OWMs, which may be a target of preformed antibody binding, leading to complement activation in OWM serum.
“In addition, data suggest that CMAH inactivation may produce a novel antigen xenogenic to the OWMs, which may be a target of preformed antibody binding, leading to complement activation in OWM serum8,9.”
From Design and testing of a humanized porcine donor for xenotransplantation (2023) · cites this paper as [9]
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Citations
Cites
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339
Lutz, A. J., Li, P., Estrada, J. L., Sidner, R. A., Chihara, R. K., Downey, S. M., Burlak, C., Wang, Z., Reyes, L. M., Ivary, B., et al. (2013) · Xenotransplantation · doi:10.1111/xen.12019 · Cited by 294
Self-citationReduced Binding of Human Antibodies to Cells From GGTA1/CMAH KO Pigs
Burlak, C., Paris, L. L., Lutz, A. J., Sidner, R. A., Estrada, J., Li, P., Tector, M., & Tector, A. J. (2014) · American Journal of Transplantation · doi:10.1111/ajt.12744 · Cited by 87
Self-citationWang, Z., Burlak, C., Estrada, J. L., Li, P., Tector, M. F., & Tector, A. J. (2014) · Xenotransplantation · doi:10.1111/xen.12106 · Cited by 64 · cited 2×
“We have shown that, with respect to human antibody binding, PBMC and erythrocytes from GGTA1/CMAH deficient swine express fewer xenoantigens than chimpanzee cells suggesting the antigenic burden on pig tissues could be reduced to concordant levels [15, 16].”
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Cited by
Sorted by citations
Design and testing of a humanized porcine donor for xenotransplantation
Anand, R. P., Layer, J. V., Heja, D., Hirose, T., Lassiter, G., Firl, D. J., Paragas, V. B., Akkad, A., Chhangawala, S., Colvin, R. B., et al. (2023) · Nature · doi:10.1038/s41586-023-06594-4 · Cited by 302
Transplanting organs from pigs to humans
Sykes, M., & Sachs, D. H. (2019) · Science Immunology · doi:10.1126/sciimmunol.aau6298 · Cited by 191
The Possible Role of Anti-Neu5Gc as an Obstacle in Xenotransplantation
Tector, A. J., Mosser, M., Tector, M., & Bach, J.-M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00622 · Cited by 60
Self-citationModifying the sugar icing on the transplantation cake
Cooper, D. K. C. (2016) · Glycobiology · doi:10.1093/glycob/cww028 · Cited by 36
Metadata
- Authors
- Estrada, J. L., Martens, G., Li, P., Adams, A., Newell, K. A., Ford, M. L., Butler, J. R., Sidner, R., Tector, M., & Tector, J.
- Venue
- Xenotransplantation
- Publisher
- Wiley
- Published
- 2015-03
- Volume
- 22
- Issue
- 3
- Pages
- 194-202
- ISSN
- 0908-665X
- 1399-3089
- PMC
- PMC4464961
- Cited by
- 417
- References
- 4
- Language
- en
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