title: Functional engraftment of human peripheral T and B cells and sustained production of autoantibodies in NOD/LtSzscid/IL-2Rγ(-/-) mice.
abstract: NOD/LtSzscid/IL-2Rγ(-/-) (NSG) mice have advantages in establishing humanized mouse models. However, transferring human PBMCs into these mice often causes lethal GVH disease. In this study, we discovered an improved method for the engraftment of normal or pathological human PBMCs into NSG mice and examined the subsequent induction of specific immune responses. We sequentially transferred human CD4+ memory T (Tm) and B cells obtained from PBMCs of healthy adults or patients with autoimmune diseases into NSG mice. Removing naïve CD4+ T cells from the transferred PBMCs allowed successful engraftment without lethal GVH disease. The transferred Tm cells were found to reside mainly in the spleen and the lymphoid nodules, where they expressed MHC class II molecules and produced cytokines, including IL-21. Surprisingly, the transferred B cells were also well maintained in the lymphoid organs, underwent de novo class-switch recombination, and secreted all isotypes of human Igs at significant levels. Moreover, transferring patient-derived Tm and B cells resulted in sustained production of IgM-rheumatoid factor and antiaminoacyl transfer RNA synthetase Abs in these mice. These results suggest that transfer of Tm and B cells derived from human PBMCs into NSG mice could be a useful method for the study of human autoimmune mechanisms.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.forename: Aoi
authors.initials: A
authors.lastname: Shiomi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kosaku
authors.initials: K
authors.lastname: Murakami
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology / Q000637:transplantation; D014183:Transplantation, Heterologous / Q000379:methods*; D000098546:Interleukin-21
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007378:Interleukins; D017493:Leukocyte Common Antigens; D000098546:Interleukin-21
keywords: Animal models; Antibodies; Autoimmunity; Immune responses; Memory cells