title: Cbl-b-deficient mice express alterations in trafficking-related molecules but retain sensitivity to the multiple sclerosis therapeutic agent, FTY720.
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.
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Mai
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Anstadt
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Kamal M
authors.initials: KM
authors.lastname: Khanna
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Medicine, University of Connecticut Health Center, Farmington, CT 06032, USA. Electronic address: rclark@nso2.uchc.edu.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clark
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D019264:Adoptive Transfer; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D000068876:Fingolimod Hydrochloride; D018398:Homeodomain Proteins / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology*; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D018398:Homeodomain Proteins; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; C064658:RAG-1 protein; D050721:Proto-Oncogene Proteins c-cbl; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Casitas-B lineage lymphoma-b; Experimental autoimmune encephalomyelitis; FTY720; Multiple sclerosis; Sphingosine-1-phosphate receptor 1; T cell trafficking
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