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

用于模拟流感感染期间人类 Fc 受体相互作用的基因人源化小鼠

基本信息

批准号：
10117188
负责人：
Beverly H Koller
金额：
$ 19.44万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-03 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117188
关键词：
Address Affinity Alleles Animals Antibodies Antibody-mediated protection CRISPR/Cas technology Cell Lineage Cells Chromosome 1 Crystallization DNA Development Disease ES Cell Line Effector Cell Ensure Epitopes Evaluation FCGR2C gene FCGR3A gene Fc Receptor Future Generations Genes Genome engineering Human IgG Receptors IgK Immune Immune response Immunity Immunoglobulin Constant Region Immunoglobulin Fragments Immunoglobulin G Immunoglobulins Individual Influenza Influenza A virus Light Mediating Modeling Modification Monoclonal Antibodies Mus Mutation Myelogenous Natural Killer Cells Orthologous Gene Pathogenesis Pathway interactions Pattern Phagocytosis Population Protein Isoforms Reagent Receptor Gene Role Structure Transgenes Transgenic Organisms Vaccinated Vaccines Validation Viral Virus anti-influenza antibody-dependent cell cytotoxicity blastocyst chimeric antibody constant region gene effectiveness evaluation embryonic stem cell homologous recombination human DNA human model human monoclonal antibodies humanized monoclonal antibodies humanized mouse improved influenza infection influenzavirus macrophage monocyte mutant neonatal Fc receptor pre-clinical receptor response species difference tool

项目摘要

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.

各种IgG的结晶区片段（Fc）之间相互作用的重要性