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Characterization of human Fc alpha receptor transgenic mice: comparison of CD89 expression and antibody-dependent
Marjolein C Stip1, J H Marco Jansen1, Maaike Nederend1
1Center for Translational Immunology, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
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, 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.
Insights
A new transgenic mouse model expressing human Fc alpha receptor (FcαRI or CD89) was developed. This model shows varied CD89 expression and IgA-mediated tumor killing capacity across mouse strains, proving useful for immunotherapy research.
Area of Science:
- Immunology
- Transgenic Models
- Fc Receptor Biology
Background:
- Mice lack the human Fc alpha receptor (FcαRI or CD89).
- A transgenic mouse model expressing human CD89 was created in four genetic backgrounds.
- Understanding this model's characteristics is crucial for its application.
Purpose of the Study:
- To characterize a novel transgenic mouse model expressing human Fc alpha receptor (FcαRI or CD89).
- To investigate CD89 expression patterns, immune cell phenotypes, and IgA-mediated anti-tumor activity.
- To determine the utility of this model for evaluating IgA-based immunotherapies.
Main Methods:
- Generation of transgenic mice expressing human CD89 in C57BL/6, BALB/c, SCID, and NXG backgrounds.
- Targeted Locus Amplification to identify transgene integration site.
- Flow cytometry to analyze CD89 expression, myeloid activation markers, and FcγRs.
- Assessment of IgA/CD89-mediated tumor cell killing capacity.
Main Results:
- The FCAR gene integrated into chromosome 4 in all mouse strains.
- CD89 expression varied across strains (highest in BALB/c and SCID, lowest in NXG) and was inducible on myeloid cells, increasing in tumor-bearing mice.
- Transgenic mice exhibited similar immune cell composition to wildtype mice.
- IgA-mediated tumor killing efficacy differed by mouse strain, influenced by neutrophil numbers and function.
Conclusions:
- The hCD89 transgenic mouse model exhibits strain-dependent characteristics relevant to FcαRI function.
- This model accurately reflects human CD89 expression patterns and IgA-mediated effector functions.
- The developed transgenic mice represent a powerful tool for preclinical testing of IgA-based immunotherapies for cancer and infectious diseases.
