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

Blood (2015-04-03)
Jeremy A Goettel, Subhabrata Biswas, Willem S Lexmond, Ada Yeste, Laura Passerini, Bonny Patel, Siyoung Yang, Jiusong Sun, Jodie Ouahed, Dror S Shouval, Katelyn J McCann, Bruce H Horwitz, Diane Mathis, Edgar L Milford, Luigi D Notarangelo, Maria-Grazia Roncarolo, Edda Fiebiger, Wayne A Marasco, Rosa Bacchetta, Francisco J Quintana, Sung-Yun Pai, Christoph Klein, Aleixo M Muise, Scott B Snapper
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
5(6)-Carboxyfluorescein diacetate N-succinimidyl ester, BioReagent, suitable for fluorescence, ≥90% (HPLC)
Sigma-Aldrich
Anti-Human IgE (ε-chain specific)−Peroxidase antibody produced in goat, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
5-Carboxy-fluorescein diacetate N-succinimidyl ester, for fluorescence, ≥95.0% (HPLC)
Sigma-Aldrich
Fluorescein, for fluorescence, free acid
Sigma-Aldrich
DAPI, for nucleic acid staining