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Published on: January 7, 2019
Cbl-b-deficient mice express alterations in trafficking-related molecules but retain sensitivity to the multiple
Mai Fujiwara1, Emily J Anstadt1, Kamal M Khanna1
1Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
Abstract:
The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these polymorphisms can be associated with abnormalities in T cell function and response to interferon-β therapy. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b(-/-)) mice show T cell abnormalities described in MS patients. We now show that Cbl-b(-/-) T cells demonstrate significant lymph node trafficking abnormalities. We thus asked whether the MS-approved drug, FTY720, postulated to trap T cells in lymphoid tissues, is less effective in the context of Cbl-b dysfunction. We now report that FTY720 significantly inhibits EAE in Cbl-b(-/-) mice. Our results newly document a role for Cbl-b in T cell trafficking but suggest nevertheless that MS patients with Cbl-b abnormalities may still be excellent candidates for FTY720 treatment.
Insights
Genetic variations in the CBLB gene impact multiple sclerosis (MS) treatment. Despite Cbl-b deficiency causing T cell issues, the MS drug FTY720 effectively treats EAE in related mouse models.
Area of Science:
- Immunology
- Neuroimmunology
- Genetics
Background:
- Multiple sclerosis (MS) treatment efficacy varies due to individual genetic differences.
- Genome-wide association studies (GWAS) link CBLB gene polymorphisms to MS susceptibility and altered T cell function.
- Cbl-b, an E3 ubiquitin ligase, regulates T cell activation; Cbl-b-deficient mice exhibit MS-like T cell abnormalities.
Purpose of the Study:
- To investigate the role of Cbl-b in T cell trafficking.
- To determine if FTY720, an MS therapeutic, is effective in a Cbl-b deficient mouse model.
- To assess the potential of FTY720 for MS patients with Cbl-b abnormalities.
Main Methods:
- Analysis of T cell lymph node trafficking in Cbl-b deficient mice.
- Evaluation of FTY720 efficacy in experimental autoimmune encephalomyelitis (EAE) in Cbl-b deficient mice.
Main Results:
- Cbl-b deficient T cells exhibit significant lymph node trafficking abnormalities.
- FTY720 treatment significantly inhibited EAE development in Cbl-b deficient mice.
- The study identified a novel role for Cbl-b in T cell trafficking.
Conclusions:
- Cbl-b plays a role in regulating T cell trafficking.
- Despite potential Cbl-b related T cell dysfunction, MS patients with CBLB abnormalities may still benefit from FTY720 therapy.
- These findings support personalized treatment strategies for multiple sclerosis.
