CTLA4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky SCID

Publication date: Available online 7 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Stéphanie Humblet-Baron, Susann Schönefeldt, Josselyn Garcia-Perez, Frédéric Baron, Emanuela Pasciuto, Adrian Liston
BackgroundSevere combined immunodeficiency (SCID) can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as RAG1, RAG2 or DCLRE1C. Defective DNA recombination causes a developmental block in T cells and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give a partial loss of T cells, in a spectrum including leaky SCID (LS) and Omenn syndrome (OS). These patients not only develop life-threatening infections due to immunodeficiency, but also develop inflammatory/autoimmune conditions due to the presence of autoreactive T cells.ObjectiveWe sought to develop a preclinical model that fully recapitulates the symptoms of LS/OS patients including a model for testing therapeutic intervention.MethodsWe generated a novel mutant mouse (Dclre1c^leaky) that develops a LS phenotype. Mice were monitored for diseases and immune phenotype and immune function were evaluated using flow cytometry, ELISA and histology.ResultsDclre1c^leaky mice present with a complete blockade of B cell differentiation, with a leaky block in T cell differentiation resulting in an oligoclonal TCR repertoire and enhanced cytokine secretion. Dclre1c^leaky mice also developed inflammatory symptoms including wasting, dermatitis, colitis, hypereosinophilia and high IgE levels. Development of a preclinical murine model for LS allowed the testing of potential treatment, with administration of CTLA4-Ig reducing disease symptoms and immunological disturbance, resulting in increased survival.ConclusionThese data suggest that CTLA4-Ig should be evaluated as a potential treatment of inflammatory symptoms in LS and OS patients.

Teaser

CTLA4-Ig controls immune dysregulation in an Artemis deficient mouse model that recapitulates leaky SCID/ Omenn Syndrome clinical manifestations.


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