title: A CB₁/CB₂ receptor agonist, WIN 55,212-2, exerts its therapeutic effect in a viral autoimmune model of multiple sclerosis by restoring self-tolerance to myelin.
abstract: Infection of mice with Theiler's murine encephalomyelitis virus (TMEV) leads to the development of TMEV-induced demyelinating disease (TMEV-IDD), an autoimmune, demyelinating and neurodegenerative pathology that serves as a model of multiple sclerosis. Activation of endogenous CB₁/CB₂ cannabinoid receptors inhibits inflammation and improves the clinical status of TMEV-IDD animals. In the present study, mice with established TMEV-IDD were treated with the CB₁/CB₂ receptor agonist WIN 55,212-2 (WIN), which restored self-tolerance to a myelin self-antigen while ameliorating the disease in a long-term manner. Accordingly, disruption of self-tolerance with cyclophosphamide provoked chronic relapse. Furthermore, transfer of splenocytes from WIN-treated TMEV-IDD mice to TMEV-infected mice at disease onset prevented the autoimmune inflammatory response and motor impairment. The therapeutic effect of WIN correlated with a decrease in the activation of CD4⁺CD25⁺Foxp3⁻ T cells and an increase in regulatory CD4⁺CD25⁺Foxp3⁺ T cells in the CNS, along with alterations in the cytokine and chemokine milieu. These findings demonstrate for the first time that the suppression of autoimmune responses to myelin antigens underlies the therapeutic effect of CB₁/CB₂ cannabinoid agonists in the treatment of multiple sclerosis.
authors.affiliation: Laboratorio de Neuroinflamación, Hospital Nacional de Paraplejicos, SESCAM, Finca la Peraleda s/n., Toledo 45071, Spain. aarevalom@sescam.jccm.es
authors.forename: Angel
authors.initials: A
authors.lastname: Arevalo-Martin
authors.forename: Eduardo
authors.initials: E
authors.lastname: Molina-Holgado
authors.forename: Carmen
authors.initials: C
authors.lastname: Guaza
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D048588:Benzoxazines / Q000627:therapeutic use*; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000276:immunology; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D009025:Morpholines / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009186:Myelin Sheath / Q000276:immunology*; D009281:Naphthalenes / Q000627:therapeutic use*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D017634:Self Tolerance / Q000187:drug effects*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D048588:Benzoxazines; D018925:Chemokines; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone