title: GM-CSF and IL-4 stimulate antibody responses in humanized mice by promoting T, B, and dendritic cell maturation.
abstract: Engraftment of human hematopoietic stem cells into immunodeficient mice that lack T cells, B cells, and NK cells results in reconstitution of human blood lineage cells, especially B cells, in the recipient mice. However, these humanized mice do not make any significant level of IgG Ab in response to Ag stimulation. In this study, we show that in humanized mice, B cells are immature, and there is a complete deficiency of CD209(+) (DC-SIGN) human dendritic cells. These defects can be corrected by expression of human GM-CSF and IL-4 in humanized mice. As a result, these cytokine-treated humanized mice produced significant levels of Ag-specific IgG after immunization, including the production of neutralizing Abs specific for H5N1 avian influenza virus. A significant level of Ag-specific CD4 T cell response was also induced. Thus, we have identified defects in humanized mice and devised approaches to correct these defects such that the platform can be used for studying Ab responses and to generate novel human Abs against virulent pathogens and other clinically relevant targets.
authors.affiliation: Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research and Technology, Singapore 138602.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.forename: Jimmy
authors.initials: J
authors.lastname: Kwang
authors.forename: Jerry K Y
authors.initials: JK
authors.lastname: Chan
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005333:Fetus; D018703:Founder Effect; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016867:Immunocompromised Host; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology; D010957:Plasmids; D059010:Single-Cell Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014162:Transfection
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; C508598:IL4 protein, human; D007074:Immunoglobulin G; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor