Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3
| Autor: | Edda Fiebiger, Scott B. Snapper, Jodie Ouahed, Maria Grazia Roncarolo, Wayne A. Marasco, Bruce H. Horwitz, Bonny Patel, Diane Mathis, Luigi D. Notarangelo, Subhabrata Biswas, Rosa Bacchetta, Aleixo M. Muise, Katelyn McCann, Jiusong Sun, Sung-Yun Pai, Ada Yeste, Laura Passerini, Jeremy A. Goettel, Dror S. Shouval, Christoph Klein, Francisco J. Quintana, Edgar L. Milford, Siyoung Yang, Willem S. Lexmond |
|---|---|
| Přispěvatelé: | Goettel, J. A., Biswas, S., Lexmond, W. S., Yeste, A., Passerini, L., Patel, B., Yang, S., Sun, J., Ouahed, J., Shouval, D. S., Mccann, K. J., Horwitz, B. H., Mathis, D., Milford, E. L., Notarangelo, L. D., Roncarolo, M., Fiebiger, E., Marasco, W. A., Bacchetta, R., Quintana, F. J., Pai, S. -Y., Klein, C., Muise, A. M., Snapper, S. B. |
| Rok vydání: | 2014 |
| Předmět: |
Immunology
Transplantation Heterologous chemical and pharmacologic phenomena Autoimmunity Enzyme-Linked Immunosorbent Assay Human leukocyte antigen Biology medicine.disease_cause Biochemistry Immunophenotyping Mice Immune system medicine Animals Humans Mice Knockout Reverse Transcriptase Polymerase Chain Reaction Autoantibody Hematopoietic Stem Cell Transplantation Immunologic Deficiency Syndromes FOXP3 Forkhead Transcription Factors Cell Biology Hematology biochemical phenomena metabolism and nutrition Immune dysregulation Flow Cytometry Immunohistochemistry Disease Models Animal Delayed hypersensitivity Humanized mouse bacteria Stem cell |
| Zdroj: | Blood. 125(25) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|