title: Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein.
abstract: BACKGROUND
  The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-β treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-β, in contrast to disease induced with Th1 where treatment attenuated symptoms.
  
  
  OBJECTIVE
  This study demonstrates the similarities between NMO and Th17 EAE and how neutrophils mediate pathology in Th17 disease.
  
  
  METHODS
  Levels of blood biomarkers in NMO were assessed by Luminex and ELISA. Effects of IFN-β on neutrophils were assessed by culture assays and immunofluorescence. EAE was induced by transfer of myelin-specific Th1 or Th17 cells and treated with Sivelestat sodium hydrate, a neutrophil elastase inhibitor.
  
  
  RESULTS
  We show Th17 cytokines, granulocyte chemokines, type 1 interferon and neutrophil elastase are elevated in patients with definitive NMO. In culture, we find that IFN-β stimulates neutrophils to release neutrophil elastase. In Th17 EAE, we demonstrate neutrophilic infiltration in the optic nerve and spinal cord which was not present in Th1 EAE. Blockade of neutrophil elastase with Sivelestat had efficacy in Th17 EAE but not Th1 EAE.
  
  
  CONCLUSIONS
  The similarities between Th17 EAE and NMO indicate that this model represents several aspects of NMO. Neutrophils are critical in the pathologies of both Th17-EAE and NMO, and therefore blockade of neutrophil elastase is a promising target in treating NMO.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Herges
authors.forename: Brigit A
authors.initials: BA
authors.lastname: de Jong
authors.forename: Ilan
authors.initials: I
authors.lastname: Kolkowitz
authors.forename: Caitlin
authors.initials: C
authors.lastname: Dunn
authors.forename: Gil
authors.initials: G
authors.lastname: Mandelbaum
authors.forename: Rose M
authors.initials: RM
authors.lastname: Ko
authors.forename: Alexander
authors.initials: A
authors.lastname: Maini
authors.forename: May H
authors.initials: MH
authors.lastname: Han
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
authors.forename: Chris
authors.initials: C
authors.lastname: Polman
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Goodyear
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Dunn
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Axtell
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D063308:Myelin-Oligodendrocyte Glycoprotein; D009471:Neuromyelitis Optica / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000276:immunology; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology; D055815:Young Adult
chemical_list: D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C445081:myelin oligodendrocyte glycoprotein (35-55); D016899:Interferon-beta; C069195:sivelestat; D010196:Pancreatic Elastase; D005998:Glycine