title: Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice.
abstract: Multiple sclerosis (MS) is a demyelinating disease of the CNS characterized by inflammation and neurodegeneration. Animal models that enable the study of remyelination in the context of ongoing inflammation are greatly needed for the development of novel therapies that target the pathological inhibitory cues inherent to the MS plaque microenvironment. We report the development of an innovative animal model combining cuprizone-mediated demyelination with transfer of myelin-reactive CD4(+) T cells. Characterization of this model reveals both Th1 and Th17 CD4(+) T cells infiltrate the CNS of cuprizone-fed mice, with infiltration of Th17 cells being more efficient. Infiltration correlates with impaired spontaneous remyelination as evidenced by myelin protein expression, immunostaining, and ultrastructural analysis. Electron microscopic analysis further reveals that demyelinated axons are preserved but reduced in caliber. Examination of the immune response contributing to impaired remyelination highlights a role for peripheral monocytes with an M1 phenotype. This study demonstrates the development of a novel animal model that recapitulates elements of the microenvironment of the MS plaque and reveals an important role for T cells and peripheral monocytes in impairing endogenous remyelination in vivo. This model could be useful for testing putative MS therapies designed to enhance remyelination in the setting of active inflammation, and may also facilitate modeling the pathophysiology of denuded axons, which has been a challenge in rodents because they typically remyelinate very quickly.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Emily G
authors.identifier: http://orcid.org/0000-0002-7238-0191
authors.initials: EG
authors.lastname: Baxi
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Joseph
authors.identifier: http://orcid.org/0000-0003-2277-2215
authors.initials: J
authors.lastname: DeBruin
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Dominique M
authors.identifier: http://orcid.org/0000-0002-9626-3950
authors.initials: DM
authors.lastname: Tosi
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Inna V
authors.initials: IV
authors.lastname: Grishkan
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Matthew D
authors.identifier: http://orcid.org/0000-0001-6614-569X
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Kirby
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Hayley J
authors.identifier: http://orcid.org/0000-0002-3026-124X
authors.initials: HJ
authors.lastname: Strasburger
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Fairchild
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 agocke4@jhu.edu pcalabr1@jhmi.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 agocke4@jhu.edu pcalabr1@jhmi.edu.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Gocke
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology* / Q000648:ultrastructure; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000628:therapy*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D020381:Interleukin-17 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D009000:Monocytes / Q000473:pathology / Q000648:ultrastructure; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D020556:Neutrophil Infiltration; D010446:Peptide Fragments / Q000633:toxicity; D012038:Regeneration / Q000187:drug effects; D058504:Th17 Cells / Q000502:physiology* / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D020381:Interleukin-17; D008996:Monoamine Oxidase Inhibitors; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D003471:Cuprizone; D005620:Freund's Adjuvant; D017493:Leukocyte Common Antigens
keywords: axons; cuprizone; demyelination; inflammation; multiple sclerosis; oligodendrocyte precursor cells