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.
Keywords:
Casitas-B lineage lymphoma-b; Experimental autoimmune encephalomyelitis; FTY720; Multiple sclerosis; Sphingosine-1-phosphate receptor 1; T cell trafficking.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / immunology
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Adoptive Transfer
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Animals
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Cell Movement / drug effects
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Cell Movement / genetics*
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Cell Movement / immunology
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Fingolimod Hydrochloride
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Homeodomain Proteins / genetics
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Immunosuppressive Agents / pharmacology*
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Immunosuppressive Agents / therapeutic use
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Lymph Nodes / drug effects
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Lymph Nodes / immunology
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Lymph Nodes / metabolism*
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / genetics
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Mice
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Mice, Knockout
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Multiple Sclerosis / drug therapy
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Multiple Sclerosis / immunology*
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Propylene Glycols / pharmacology*
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Propylene Glycols / therapeutic use
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Proto-Oncogene Proteins c-cbl / genetics*
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Proto-Oncogene Proteins c-cbl / immunology
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Sphingosine / therapeutic use
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Cblb protein, mouse
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Homeodomain Proteins
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Immunosuppressive Agents
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Propylene Glycols
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RAG-1 protein
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Proto-Oncogene Proteins c-cbl
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Fingolimod Hydrochloride
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Sphingosine