Characterization of human Fc alpha receptor transgenic mice: comparison of CD89 expression and antibody-dependent tumor killing between mouse strains
Stip, Marjolein C; Jansen, J H Marco; Nederend, Maaike; Tsioumpekou, Maria; Evers, Mitchell; Olofsen, Patricia A; Meyer-Wentrup, Friederike; Leusen, Jeanette H W
(2023) Cancer Immunology, Immunotherapy, volume 72, issue 9, pp. 3063 - 3077
(Article)
Abstract
Since mice do not express a homologue of the human Fc alpha receptor (FcαRI or CD89), a transgenic mouse model was generated in four different backgrounds (C57BL/6, BALB/c, SCID and NXG) expressing the FcαRI under the endogenous human promoter. In this study, we describe previously unknown characteristics of this model,
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such as the integration site of the FCAR gene, the CD89 expression pattern in healthy male and female mice and in tumor-bearing mice, expression of myeloid activation markers and FcγRs and IgA/CD89-mediated tumor killing capacity. In all mouse strains, CD89 expression is highest in neutrophils, intermediate on other myeloid cells such as eosinophils and DC subsets and inducible on, among others, monocytes, macrophages and Kupffer cells. CD89 expression levels are highest in BALB/c and SCID, lower in C57BL/6 and lowest in NXG mice. Additionally, CD89 expression on myeloid cells is increased in tumor-bearing mice across all mouse strains. Using Targeted Locus Amplification, we determined that the hCD89 transgene has integrated in chromosome 4. Furthermore, we established that wildtype and hCD89 transgenic mice have a similar composition and phenotype of immune cells. Finally, IgA-mediated killing of tumor cells is most potent with neutrophils from BALB/c and C57BL/6 and less with neutrophils from SCID and NXG mice. However, when effector cells from whole blood are used, SCID and BALB/c are most efficient, since these strains have a much higher number of neutrophils. Overall, hCD89 transgenic mice provide a very powerful model to test the efficacy of IgA immunotherapy against infectious diseases and cancer.
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Keywords: Fc alpha receptor, Genetically engineered mouse model, Immunoglobulin A, Immunotherapy, Neutrophils, Oncology, Cancer Research, Immunology and Allergy, Immunology, Journal Article
ISSN: 0340-7004
Publisher: Springer Science and Business Media Deutschland GmbH
Note: Funding Information: We thank the flow cytometry facility in the UMCU for their service and the GDL laboratory for excellent care of the laboratory animals. We thank Cergentis for performing the TLA analysis, Craig Morton of the Institute of Marine Research in Bergen for his help determining the FCAR insert, and Thomas Valerius of the University of Kiel for encouraging us to breed the FcaRI transgenic mice in the NXG background. We would like to thank Mick van Eijs, Rik Verheijden, Karijn Suijkerbuijk and the UNICIT consortium for kindly providing patient material for this study. Funding Information: MCS and MN were funded by Villa Joep (project 17 IgA and anti-GD2). JHMJ, MN, MT and PAO were funded by the KWF Dutch Cancer Society: Grant number 9038 / 2021-PPS. Publisher Copyright: © 2023, The Author(s).
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