title: Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis.
abstract: BACKGROUND
  Tumor necrosis factor (TNF) has pleiotropic functions during both the demyelinating autoimmune disease multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE). How TNF regulates disability during progressive disease remains unresolved. Using a progressive EAE model characterized by sustained TNF and increasing morbidity, this study evaluates the role of unregulated TNF in exacerbating central nervous system (CNS) pathology and inflammation.
  
  
  METHODS
  Progressive MS was mimicked by myelin oligodendrocyte glycoprotein (MOG) peptide immunization of mice expressing a dominant negative IFN-γ receptor alpha chain under the human glial fibrillary acidic protein promoter (GFAPγR1∆). Diseased GFAPγR1∆ mice were treated with anti-TNF or control monoclonal antibody during acute disease to monitor therapeutic effects on sustained disability, demyelination, CNS inflammation, and blood brain barrier (BBB) permeability.
  
  
  RESULTS
  TNF was specifically sustained in infiltrating macrophages. Anti-TNF treatment decreased established clinical disability and mortality rate within 7 days. Control of disease progression was associated with a decline in myelin loss and leukocyte infiltration, as well as macrophage activation. In addition to mitigating CNS inflammation, TNF neutralization restored BBB integrity and enhanced CNS anti-inflammatory responses.
  
  
  CONCLUSIONS
  Sustained TNF production by infiltrating macrophages associated with progressive EAE exacerbates disease severity by promoting inflammation and disruption of BBB integrity, thereby counteracting establishment of an anti-inflammatory environment required for disease remission.
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA. valenta@ccf.org.
authors.forename: Alice
authors.initials: A
authors.lastname: Valentin-Torres
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA. savaric@ccf.org.
authors.forename: Carine
authors.initials: C
authors.lastname: Savarin
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. dhinton@usc.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.affiliation: Malaria Vaccine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA. timothy.w.phares.ctr@mail.mil.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Phares
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA. bergmac@ccf.org.
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA. stohlms2@ccf.org.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000235:genetics; D002490:Central Nervous System / Q000473:pathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D009457:Neuroglia / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: C491049:Aif1 protein, mouse; D000906:Antibodies; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma