Format

Send to

Choose Destination
Blood. 2015 Jun 18;125(25):3886-95. doi: 10.1182/blood-2014-12-618363. Epub 2015 Apr 1.

Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3.

Author information

1
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
2
Department of Medicine, Harvard Medical School, Boston, MA; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA;
3
Department of Medicine, Harvard Medical School, Boston, MA; Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA;
4
Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy;
5
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA;
6
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA;
7
Department of Medicine, Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital, Boston, MA;
8
Department of Medicine, Harvard Medical School, Boston, MA; Renal Division and Tissue Typing Laboratory, Brigham and Women's Hospital, Boston, MA;
9
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;
10
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;
11
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;
12
Department of Pediatrics, Dr von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany;
13
Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada; and.
14
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.

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.

Comment in

PMID:
25833964
PMCID:
PMC4473116
DOI:
10.1182/blood-2014-12-618363
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center