title: Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration.
abstract: OBJECTIVE
  Experimental autoimmune encephalomyelitis (EAE) is a CD4(+)-mediated autoimmune pathology of the central nervous system (CNS) that is used as a model for the study of the human neuroinflammatory disease, multiple sclerosis. During the development of EAE, auto-reactive Th1 and Th17 CD4(+) T cells infiltrate the CNS promoting inflammatory cells recruitment, focal inflammation and tissue destruction. In this sense, statins, agents used to lower lipid levels, have recently shown to exert interesting immunomodulatory function. In fact, statins promote a bias towards a Th2 response, which ameliorates the clinical outcome of EAE. Additionally, simvastatin can inhibit Th17 differentiation. However, many other effects exerted on the immune system by statins have yet to be clarified, in particular during neuroinflammation. Thus, the aim of this study was to investigate the effects of simvastatin on the development of experimental autoimmune encephalomyelitis.
  
  
  METHODS
  Mice were immunized with MOG(35-55) and EAE severity was assessed daily and scored using a clinical scale. Cytokine secretion by mononuclear cells infiltrating the CNS was evaluated by flow cytometry.
  
  
  RESULTS
  Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-β mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1β secretion (p < 0.05). This was accompanied by a significant decrease in CNS inflammatory mononuclear cell infiltration, with reduced frequencies of both Th1 and Th17 cells. Simvastatin inhibited the proliferation of T lymphocytes co-cultured with primary microglial cells.
  
  
  CONCLUSIONS
  Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.
authors.affiliation: Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo, SP, 05508-900, Brazil. daniel-larissa@hotmail.com.|Laboratory for Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo (USP), São Paulo, SP, 05508-090, Brazil. daniel-larissa@hotmail.com.
authors.forename: Daniel May
authors.initials: DM
authors.lastname: de Oliveira
authors.affiliation: Discipline of Clinical Neurology, Federal University of São Paulo UNIFESP, São Paulo, SP, 04023-900, Brazil.
authors.forename: Enedina Maria Lobato
authors.initials: EM
authors.lastname: de Oliveira
authors.affiliation: Department of Genetics and Evolutive Biology, Biosciences Institute, University of São Paulo (USP), São Paulo, SP, 05508-090, Brazil.
authors.forename: Merari de Fátima Ramires
authors.initials: Mde F
authors.lastname: Ferrari
authors.affiliation: Biosciences Institute, University of São Paulo, São Paulo, SP, 05508-900, Brazil.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Semedo
authors.affiliation: Laboratory for Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo (USP), São Paulo, SP, 05508-090, Brazil.
authors.forename: Meire Ioshie
authors.initials: MI
authors.lastname: Hiyane
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Medicine Department, Federal University of São Paulo UNIFESP, São Paulo, SP, 04023-900, Brazil.
authors.forename: Marcos Antônio
authors.initials: MA
authors.lastname: Cenedeze
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Medicine Department, Federal University of São Paulo UNIFESP, São Paulo, SP, 04023-900, Brazil.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pacheco-Silva
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Nephrology Division, Medicine Department, Federal University of São Paulo UNIFESP, São Paulo, SP, 04023-900, Brazil.|Laboratory for Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo (USP), São Paulo, SP, 05508-090, Brazil.
authors.forename: Niels Olsen Saraiva
authors.initials: NO
authors.lastname: Câmara
authors.affiliation: Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo, SP, 05508-900, Brazil.
authors.forename: Jean Pierre Schatzmann
authors.initials: JP
authors.lastname: Peron
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology; D018946:Chemokine CCL5 / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D019821:Simvastatin / Q000276:immunology / Q000494:pharmacology*; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D018946:Chemokine CCL5; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D019821:Simvastatin
keywords: Chemokine; Experimental autoimmune encephalomyelitis; Proliferation; Simvastatin; Th1; Th17