دورية أكاديمية
Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky severe combined immunodeficiency
| العنوان: | Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky severe combined immunodeficiency |
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| المؤلفون: | Humblet-Baron, Stephanie, Schönefeldt, Susan, Garcia-Perez, Josselyn E, Baron, Frédéric, Pasciuto, Emanuela, Liston, Adrian |
| المصدر: | Journal of Allergy and Clinical Immunology, 140 (5), 1394-1403.e8 (2017-11) |
| بيانات النشر: | Mosby, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | leaky-SCID, Treg, Artemis, immune dysregulation, regulatory T cell, cytotoxic T-lymphocyte-associated protein 4, Leaky severe combined immunodeficiency, CTLA4, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse |
| الوصف: | BACKGROUND: Severe combined immunodeficiency can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as recombination-activating gene 1 (RAG1), RAG2, or DNA cross-link repair 1C (DCLRE1C). Defective DNA recombination causes a developmental block in T and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give rise to a partial loss of T cells in a spectrum including leaky severe combined immunodeficiency (LS) and Omenn syndrome (OS). These patients not only experience life-threatening infections because of immunodeficiency but also experience inflammatory/autoimmune conditions caused by the presence of autoreactive T cells. OBJECTIVE: We sought to develop a preclinical model that fully recapitulates the symptoms of patients with LS/OS, including a model for testing therapeutic intervention. METHODS: We generated a novel mutant mouse (Dclre1cleaky) that develops a LS phenotype. Mice were monitored for diseases, and immune phenotype and immune function were evaluated by using flow cytometry, ELISA, and histology. RESULTS: Dclre1cleaky mice present with a complete blockade of B-cell differentiation, with a leaky block in T-cell differentiation resulting in an oligoclonal T-cell receptor repertoire and enhanced cytokine secretion. Dclre1cleaky mice also had inflammatory symptoms, including wasting, dermatitis, colitis, hypereosinophilia, and high IgE levels. Development of a preclinical murine model for LS allowed testing of potential treatment, with administration of cytotoxic T-lymphocyte-associated protein 4-Ig reducing disease symptoms and immunologic disturbance, resulting in increased survival. CONCLUSION: These data suggest that cytotoxic T-lymphocyte-associated protein 4-Ig should be evaluated as a potential treatment of inflammatory symptoms in patients with LS and those with OS. |
| نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501 article |
| اللغة: | English |
| Relation: | urn:issn:0091-6749; urn:issn:1097-6825 |
| DOI: | 10.1016/j.jaci.2016.12.968 |
| URL الوصول: | https://orbi.uliege.be/handle/2268/208166 |
| حقوق: | open access http://purl.org/coar/access_right/c_abf2 info:eu-repo/semantics/openAccess |
| رقم الأكسشن: | edsorb.208166 |
| قاعدة البيانات: | ORBi |
| DOI: | 10.1016/j.jaci.2016.12.968 |
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