Mouse model recapitulating human Fcγ receptor structural and functional diversity
Open Access
- 2 April 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (16), 6181-6186
- https://doi.org/10.1073/pnas.1203954109
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.Keywords
This publication has 27 references indexed in Scilit:
- Epidermal Growth Factor Receptor (EGFR) Antibody-Induced Antibody-Dependent Cellular Cytotoxicity Plays a Prominent Role in Inhibiting Tumorigenesis, Even of Tumor Cells Insensitive to EGFR Signaling InhibitionThe Journal of Immunology, 2011
- FcγR polymorphisms: Implications for function, disease susceptibility and immunotherapyTissue Antigens, 2003
- Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targetsNature Medicine, 2000
- Reconstitution of human Fc gamma RIII cell type specificity in transgenic mice.The Journal of Experimental Medicine, 1996
- Antigen targeting to myeloid-specific human Fc gamma RI/CD64 triggers enhanced antibody responses in transgenic mice.JCI Insight, 1996
- Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.The Journal of Experimental Medicine, 1992
- Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function.JCI Insight, 1992
- Molecular basis for a polymorphism of human Fc gamma receptor II (CD32).The Journal of Experimental Medicine, 1990
- Alternative membrane forms of Fc gamma RIII(CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions.The Journal of Experimental Medicine, 1989
- The Fc receptor, FcRI, and other activation molecules on human mononuclear phagocytes after treatment with interferon-gamma.1989