# Genetically humanized mice for modeling human Fc-receptor interaction during influenza infection

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $233,250

## Abstract

The importance of interactions between the fragment of crystallization (Fc) region of various IgG
isoforms and the array of FcγRs expressed by effector immune cells in establishment of broad
immunity to influenza viruses is increasingly recognized. However, the translational value of
studies of these pathways in mice is limited in part by major species differences in the number,
structure and expression pattern of the FcγRs, particularly the low affinity receptors clustered on
chromosome 1. Similarly, although both the mouse and the human IgG locus encode four IgG
constant region genes and thus produce four IgG isotypes, divergence between the species has
made it difficult to assign mouse orthologs to human IgG constant region genes. These species
differences have also limited the use of the mouse as a preclinical tool for evaluating reagents
such as vaccines and humanized monoclonal antibodies (mAbs).To address this, we have
generated mice in which the three loci encoding mouse IgG receptors, FcɣRII/III/IV, FcɣR1a,
and FcRn (the IgG transporter), are humanized by syntenic replacement. Mice humanized for
the FCɣRs and derived lines expressing only one of the three low affinity FCGR activating
receptor genes, FCGR2A, FCGR2C or FCGR3A, will be used to evaluate the role of these
receptors in antibody-mediated protection against influenza. The contribution of human Fc
receptors would ideally be studied in animals in which the IgG isotypes produced in response to
virus have human Fc regions, ensuring that the Fc-FCɣR interactions mimic those observed in
humans. We address this limitation by humanization of the ~200 kb mouse IgH constant region,
as well as the constant region for the kappa light chains. As embryonic stem cells from mice
humanized for the FCGR genes are used for this genome engineering, the mice generated will
not only produce human IgG isoforms, but these isoforms will interact with human effector
FCɣRs on effector cell populations.These animals will provide a model for evaluation of the
effectiveness of human mAbs as well as for defining Fc-FcɣR pathways whose engagement
modulates the pathogenesis of disease after viral exposure and/or improves immunity in
vaccinated animals.

## Key facts

- **NIH application ID:** 9960123
- **Project number:** 1R21AI151231-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Beverly H Koller
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2020-03-03 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960123

## Citation

> US National Institutes of Health, RePORTER application 9960123, Genetically humanized mice for modeling human Fc-receptor interaction during influenza infection (1R21AI151231-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9960123. Licensed CC0.

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