title: Mouse model recapitulating human Fcγ receptor structural and functional diversity.
abstract: The in vivo biological activities of IgG antibodies result from their bifunctional nature, in which antigen recognition by the Fab is coupled to the effector and immunomodulatory diversity found in the Fc domain. This diversity, resulting from both amino acid and glycan heterogeneity, is translated into cellular responses through Fcγ receptors (FcγRs), a structurally and functionally diverse family of cell surface receptors found throughout the immune system. Although many of the overall features of this system are maintained throughout mammalian evolution, species diversity has precluded direct analysis of human antibodies in animal species, and, thus, detailed investigations into the unique features of the human IgG antibodies and their FcγRs have been limited. We now report the development of a mouse model in which all murine FcγRs have been deleted and human FcγRs, encoded as transgenes, have been inserted into the mouse genome resulting in recapitulation of the unique profile of human FcγR expression. These human FcγRs are shown to function to mediate the immunomodulatory, inflammatory, and cytotoxic activities of human IgG antibodies and Fc engineered variants and provide a platform for the detailed mechanistic analysis of therapeutic and pathogenic IgG antibodies.
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: David J
authors.initials: DJ
authors.lastname: DiLillo
authors.forename: Stylianos
authors.initials: S
authors.lastname: Bournazos
authors.forename: Fubin
authors.initials: F
authors.lastname: Li
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D020033:Protein Isoforms; D017452:Receptors, IgG