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Human CD31 on porcine cells suppress xenogeneic neutrophil-mediated cytotoxicity via the inhibition of NETosis.
- Source :
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Xenotransplantation [Xenotransplantation] 2018 Sep; Vol. 25 (5), pp. e12396. Date of Electronic Publication: 2018 Apr 08. - Publication Year :
- 2018
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Abstract
- Background: Xenotransplantation is one of the promising strategies for overcoming the shortage of organs available for transplant. However, many immunological obstructions need to be overcome for practical use. Increasing evidence suggests that neutrophils contribute to xenogeneic cellular rejection. Neutrophils are regulated by activation and inhibitory signals to induce appropriate immune reactions and to avoid unnecessary immune reactivity. Therefore, we hypothesized that the development of neutrophil-targeted therapies may have the potential for increased graft survival in xenotransplantation.<br />Methods: A plasmid containing a cDNA insert encoding the human CD31 gene was transfected into swine endothelial cells (SEC). HL-60 cells were differentiated into neutrophil-like cells by culturing them in the presence of 1.3% dimethyl sulfoxide for 48 hours. The cytotoxicity of the differentiated HL-60 cells (dHL-60) and peripheral blood-derived neutrophils was evaluated by WST-8 assays. To investigate the mechanism responsible for hCD31-induced immunosuppression, citrullinated histone 3 (cit-H3) and phosphorylation of SHP-1 were detected by a cit-H3 enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively.<br />Results: A significant decrease in dHL-60 and neutrophil-mediated cytotoxicity in SEC/hCD31 compared with SEC was seen, as evidenced by a cytotoxicity assay. Furthermore, the suppression of NETosis and the induction of SHP-1 phosphorylation in neutrophils that had been co-cultured with SEC/CD31 were confirmed by cit-H3 ELISA and Western blotting with an anti-phosphorylated SHP-1.<br />Conclusion: These data suggest that human CD31 suppresses neutrophil-mediated xenogenic cytotoxicity via the inhibition of NETosis. As CD31 is widely expressed in a variety of inflammatory cells, human CD31-induced suppression may cover the entire xenogeneic cellular rejection, thus making the generation of human CD31 transgenic pigs very attractive for use in xenografts.<br /> (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Subjects :
- Animals
Animals, Genetically Modified immunology
Humans
Immunosuppression Therapy methods
Macrophages immunology
Swine
Transplantation, Heterologous methods
Cytotoxicity, Immunologic immunology
Endothelial Cells immunology
Neutrophils immunology
Platelet Endothelial Cell Adhesion Molecule-1 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1399-3089
- Volume :
- 25
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Xenotransplantation
- Publication Type :
- Academic Journal
- Accession number :
- 29635708
- Full Text :
- https://doi.org/10.1111/xen.12396