title: CpG Type A Induction of an Early Protective Environment in Experimental Multiple Sclerosis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS), and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immunity is clearly pivotal in the pathogenesis of EAE, with an essential role of CD4+T cells, little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs), typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs). In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type A ODN (CpG-A), known to induce high amounts of IFN-αin pDCs, significantly reduced disease severity in EAE, relative to controls (12.63 ± 1.86 versus 23.49 ± 1.46, resp.;p= 0.001). Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+CD4+) T cells. CpG-A likewise reduced the levels of IL-17 and IFN-γin the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A-treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms.
authors.affiliation: Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham, UK.
authors.forename: James
authors.initials: J
authors.lastname: Crooks
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gargaro
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Claudia
authors.identifier: 0000-0002-3967-7954
authors.initials: C
authors.lastname: Volpi
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pirro
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Scalisi
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Turco
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Romani
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Matino
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.identifier: 0000-0001-6674-2128
authors.initials: P
authors.lastname: Puccetti
authors.affiliation: Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham, UK; Department of Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gran
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Francesca
authors.identifier: 0000-0002-8501-2136
authors.initials: F
authors.lastname: Fallarino
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000166:cytology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D007249:Inflammation; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
chemical_list: C408982:CPG-oligonucleotide; D004731:Endotoxins; D008024:Ligands; D009838:Oligodeoxyribonucleotides