title: A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production.
abstract: Humanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen-specific antibody responses. Here we describe a new mouse strain, in which human interleukin 6 (IL-6) gene encoding the cytokine that is important for B- and T-cell differentiation was knocked into its respective mouse locus. The provision of human IL-6 not only enhanced thymopoiesis and periphery T-cell engraftment, but also significantly increased class switched memory B cells and serum immunoglobulin G (IgG). In addition, immunization with ovalbumin (OVA) induced OVA-specific B cells only in human IL-6 knock-in mice. These OVA-specific antibodies displayed the highest frequency of somatic mutation, further suggesting that human IL-6 is important for efficient B-cell activation and selection. We conclude that human IL-6 knock-in mice represent a novel and improved model for human adaptive immunity without relying on complex surgery to transplant human fetal thymus and liver. These mice can therefore be used to exploit or evaluate immunization regimes that would be unethical or untenable in humans.
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.
authors.forename: Hua
authors.identifier: 0000-0002-1691-2763
authors.initials: H
authors.lastname: Yu
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Borsotti
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Eynon
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY; and.
authors.forename: Davor
authors.initials: D
authors.lastname: Frleta
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY; and.
authors.forename: Cagan
authors.initials: C
authors.lastname: Gurer
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY; and.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: Division of Hematology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT.|Howard Hughes Medical Institute, Yale University, New Haven, CT.
authors.forename: Richard A
authors.identifier: 0000-0003-4461-0778
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002645:Chickens; D015870:Gene Expression; D055879:Gene Knock-In Techniques / Q000379:methods; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007114:Immunization; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: C508600:IL6 protein, human; D007074:Immunoglobulin G; D015850:Interleukin-6; D010047:Ovalbumin