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Cited by 33Xenotransplantation and immune responseGlycosylation and Glycoproteins ResearchAnimal Genetics and Reproduction

Both Natural and Induced Anti-Sda Antibodies Play Important Roles in GTKO Pig-to-Rhesus Monkey Xenotransplantation

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Feng, Hao, Li, Tao, Du, Jiaxiang, Xia, Qiangbing, Wang, Lu, Chen, Song, Zhu, Lan, Pan, Dengke +2 more·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.849711PMC PMC9004458
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Abstract

Sda, produced by the B4GALNT2 enzyme, has been recognized as an important xenoantigen for pig-to-nonhuman primate xenotransplantation. However, little is known about Sda expression in pigs and its immunogenicity in xenotransplantation. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from wildtype, GTKO (with high, moderate, and low Sda expression), GTKO/β4GalNT2KO, GTKO/CMAHKO, or GTKO/CMAHKO/β4GalNT2KO pigs. Anti-pig IgM/IgG binding and complement-dependent cytotoxicity (CDC) to pig PBMCs was measured by flow cytometry using pooled rhesus monkey sera (n=20) or human sera (n=20). As compared to wild-type pigs (n=12), GTKO pigs (n=17) had a significantly higher mean level of Sda expression on PBMCs and showed a greater individual difference in expression. Both the overall binding of monkey serum IgM/IgG antibody to GTKO pig PBMCs and CDC against these PBMCs decreased significantly with a progressive reduction in Sda expression, showing a clear dose-effect relationship. Both the monkey serum antibody binding and CDC decreased significantly after the additional deletion of Sda, whereas the binding of human serum antibody and CDC against the GTKO pig PBMCs were markedly reduced after the deletion of Neu5Gc in the pigs. In addition, anti-Sda antibody accounted for > 50% of the induced anti-non-Gal antibody at the time of rejection in two rhesus monkeys that received GTKO/hCD55 pig kidney xenotransplantation, and the anti-Sda antibody showed significant cytotoxic activity against GTKO pig cells. We conclude that both natural and induced anti-Sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation, thus providing further evidence for GTKO/β4GalNT2KO pigs as the preferred organ source for rhesus monkeys as a preclinical model of xenotransplantation.

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  • Incubation of pig peripheral blood mononuclear cells with human and monkey sera demonstrated that the Sda antigen is immunogen in a dose-dependent manner.

    “Incubation of pig peripheral blood mononuclear cells with human and monkey sera demonstrated that the Sda antigen is immunogen in a dose-dependent manner.”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [145]

    The Results section on monkey-serum binding reports that antibody binding and cytotoxicity against GTKO pig PBMCs decreased as Sda expression fell, supporting a dose-dependent effect for monkey serum. The Results section comparing human and monkey sera instead identifies Neu5Gc as the main determinant of human-serum reactivity. These incubation experiments measure binding and cytotoxicity, not dose-dependent induction of an immune response. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Feng, H., Li, T., Du, J., Xia, Q., Wang, L., Chen, S., Zhu, L., Pan, D., Wang, Y., & Chen, G.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Hainan Medical University (CN)
  • Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (CN)
Corresponding author
  • Pan, Dengke
  • Wang, Yi
  • Chen, Gang
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-03-29
Volume
13
Pages
849711-849711
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.849711
PMC
PMC9004458
OpenAlex
W4220848368
Cited by
33
References
1
Citations by year
2026: 6 · 2025: 7 · 2024: 10 · 2023: 6 · 2022: 4
FWCI
6.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
Keywords
SDA, xenoantigens, CMAH, N-glycolylneuraminic acid, complement-dependent cytotoxicity, xenotransplant rejection, peripheral blood mononuclear cells
MeSH terms
Animals, Immunoglobulin M, Leukocytes, Mononuclear, Macaca mulatta, Swine, Transplantation, Heterologous, Animals, Genetically Modified

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