Abstract
Antibodies of the IgG isotype have a variety of pro- and anti-inflammatory effector functions, making them attractive platforms for the development of novel therapeutic approaches. Animal model systems have been invaluable to the understanding of the underlying mechanisms of IgG activity. However, differences in the IgG subclasses and Fc receptors responsible for mediating IgG-dependent effector functions, even between such closely related species as humans and monkeys, make it difficult to predict the activity of human IgG in vivo. This review will focus on currently available animal model systems used to study human IgG activity and will propose novel model systems that might enable us to obtain a closer look at the molecular and cellular mechanisms underlying human IgG activity in vivo.
Similar content being viewed by others
References
Nimmerjahn F, Ravetch JV. Antibody-mediated modulation of immune responses. Immunol Rev. 2010;236:265–75.
Ruuls SR, Lammerts van Bueren JJ, van de Winkel JG, Parren PW. Novel human antibody therapeutics: the age of the Umabs. Biotechnol J. 2008;3:1157–71.
Peterson C. Drug therapy of cancer. Eur J Clin Pharmacol. 2011;67:437–47.
Hirano M, Davis RS, Fine WD, Nakamura S, Shimizu K, Yagi H, et al. IgEb immune complexes activate macrophages through FcgammaRIV binding. Nat Immunol. 2007;8:762–71.
Mancardi DA, Iannascoli B, Hoos S, England P, Daeron M, Bruhns P. FcgammaRIV is a mouse IgE receptor that resembles macrophage FcepsilonRI in humans and promotes IgE-induced lung inflammation. J Clin Invest. 2008;118:3738–50.
Bruhns P, Iannascoli B, England P, Mancardi DA, Fernandez N, Jorieux S, et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. 2009;113:3716–25.
Breunis WB, van Mirre E, Bruin M, Geissler J, de Boer M, Peters M, et al. Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood. 2008;111:1029–38.
Pallardy M, Hunig T. Primate testing of TGN1412: right target, wrong cell. Br J Pharmacol. 2010;161:509–11.
Ahuja A, Shupe J, Dunn R, Kashgarian M, Kehry MR, Shlomchik MJ. Depletion of B cells in murine lupus: efficacy and resistance. J Immunol. 2007;179:3351–61.
Yazawa N, Hamaguchi Y, Poe JC, Tedder TF. Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease. Proc Natl Acad Sci U S A. 2005;102:15178–83.
Honeychurch J, Tutt AL, Valerius T, Heijnen IA, Van De Winkel JG, Glennie MJ. Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma. Blood. 2000;96:3544–52.
Li M, Wirthmueller U, Ravetch JV. Reconstitution of human Fc gamma RIII cell type specificity in transgenic mice. J Exp Med. 1996;183:1259–63.
Tan Sardjono C, Mottram PL, Hogarth PM. The role of FcgammaRIIa as an inflammatory mediator in rheumatoid arthritis and systemic lupus erythematosus. Immunol Cell Biol. 2003;81:374–81.
Li F, Ravetch JV. Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science. 2011;333:1030–4.
Stavenhagen JB, Gorlatov S, Tuaillon N, Rankin CT, Li H, Burke S, et al. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. Cancer Res. 2007;67:8882–90.
Smith P, DiLillo DJ, Bournazos S, Li F, Ravetch JV. Mouse model recapitulating human Fcγ receptor structural and functional diversity. Proc Natl Acad Sci U S A. 2012;109:6181–6.
Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7:118–30.
Becker PD, Legrand N, van Geelen CM, Noerder M, Huntington ND, Lim A, et al. Generation of human antigen-specific monoclonal IgM antibodies using vaccinated "human immune system" mice. PLoS One. 2010;5.
Maenaka K, van der Merwe PA, Stuart DI, Jones EY, Sondermann P. The human low affinity Fcgamma receptors IIa, IIb, and III bind IgG with fast kinetics and distinct thermodynamic properties. J Biol Chem. 2001;276:44898–904.
Okazaki A, Shoji-Hosaka E, Nakamura K, Wakitani M, Uchida K, Kakita S, et al. Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate between IgG1 and FcgammaRIIIa. J Mol Biol. 2004;336:1239–49.
Paetz A, Sack M, Thepen T, Tur MK, Bruell D, Finnern R, et al. Recombinant soluble human Fcgamma receptor I with picomolar affinity for immunoglobulin G. Biochem Biophys Res Commun. 2005;338:1811–7.
Acknowledgements
This study was supported by grants from the German Research Foundation (SFB 643, GK1660, FOR832, SPP1468) and from the Bavarian Genome Research Network (BayGene). We apologize to all colleagues whose important work could not be cited due to limitations in space.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lux, A., Nimmerjahn, F. Of Mice and Men: The Need for Humanized Mouse Models to Study Human IgG Activity in Vivo. J Clin Immunol 33 (Suppl 1), 4–8 (2013). https://doi.org/10.1007/s10875-012-9782-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-012-9782-0