Reference : Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation...
Scientific journals : Article
Human health sciences : Immunology & infectious disease
Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky severe combined immunodeficiency
Humblet-Baron, Stephanie [> >]
Schönefeldt, Susan [> >]
Garcia-Perez, Josselyn E [> >]
Baron, Frédéric mailto [Université de Liège > > GIGA-R : Hématologie >]
Pasciuto, Emanuela [> >]
Liston, Adrian [> >]
In press
Journal of Allergy and Clinical Immunology (The)
Yes (verified by ORBi)
St Louis
[en] leaky-SCID ; Treg ; CTLA4
[en] Background: Severe 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.
Objective: We sought to develop a preclinical model that fully
recapitulates the symptoms of LS/OS patients including a model for
testing therapeutic intervention.
Methods: We 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.
Results: Dclre1c 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.
Conclusion: These data suggest that CTLA4-Ig should be evaluated as a
potential treatment of inflammatory symptoms in LS and OS patients.

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