title: Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3.
abstract: Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goettel
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Willem S
authors.initials: WS
authors.lastname: Lexmond
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA;
authors.forename: Ada
authors.initials: A
authors.lastname: Yeste
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy;
authors.forename: Laura
authors.initials: L
authors.lastname: Passerini
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA;
authors.forename: Bonny
authors.initials: B
authors.lastname: Patel
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA;
authors.forename: Siyoung
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Jodie
authors.initials: J
authors.lastname: Ouahed
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Dror S
authors.initials: DS
authors.lastname: Shouval
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA;
authors.forename: Katelyn J
authors.initials: KJ
authors.lastname: McCann
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA;
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Renal Division and Tissue Typing Laboratory, Brigham and Women's Hospital, Boston, MA;
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Milford
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Division of Immunology and The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA;
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy;
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Edda
authors.initials: E
authors.lastname: Fiebiger
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy;
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA;
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA; Division of Hematology-Oncology, Boston Children's Hospital, Boston, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Sung-Yun
authors.initials: SY
authors.lastname: Pai
authors.affiliation: Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada; and.
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007150:Immunohistochemistry; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
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