title: Dose-dependent inhibition of demyelination and microglia activation by IVIG.
abstract: Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Clinical trials of IVIG for multiple sclerosis, using diverse dose regimens, yielded controversial results. The aim of this study is to dissect IVIG effector mechanisms on demyelination in anex vivomodel of the central nervous system (CNS)-immune interface.
  
  
  
  Using organotypic cerebellar slice cultures (OSC) from transgenic mice expressing green fluorescent protein (GFP) in oligodendrocytes/myelin, we induced extensive immune-mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective IVIG effects were assessed by live imaging of GFP expression, confocal microscopy, immunohistochemistry, gene expression analysis and flow cytometry.
  
  
  
  IVIG protected OSC from demyelination in a dose-dependent manner, which was at least partly attributed to interference with complement-mediated oligodendroglia damage, while binding of the anti-MOG antibody was not prevented. Staining with anti-CD68 antibodies and flow cytometry confirmed that IVIG prevented microglia activation and oligodendrocyte death, respectively. Equimolar IVIG-derived Fab fragments or monoclonal IgG did not protect OSC, while Fc fragments derived from a polyclonal mixture of human IgG were at least as potent as intact IVIG.
  
  
  
  Both intact IVIG and Fc fragments exert a dose-dependent protective effect on antibody-mediated CNS demyelination and microglia activation by interfering with the complement cascade and, presumably, interacting with local immune cells. Although this experimental model lacks blood-brain barrier and peripheral immune components, our findings warrant further studies on optimal dose finding and alternative modes of application to enhance local IVIG concentrations at the site of tissue damage.
authors.affiliation: Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5 D-40225 Duesseldorf Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Winter
authors.affiliation: Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5 D-40225 Duesseldorf Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Baksmeier
authors.affiliation: Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5 D-40225 Duesseldorf Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Steckel
authors.affiliation: Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5 D-40225 Duesseldorf Germany.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Barman
authors.affiliation: Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5D-40225 Duesseldorf Germany; Present address: CPTP, Centre Physiopathologie de Toulouse-Purpan INSERM U1043 - CNRS UMR 5282-Université Toulouse III Toulouse France.
authors.forename: Manish
authors.initials: M
authors.lastname: Malviya
authors.affiliation: University of Zuerich, Clinical Neuroimmunology Zuerich Switzerland; Present address: Abb Vie AG Baar Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Harrer-Kuster
authors.affiliation: Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5 D-40225 Duesseldorf Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf Moorenstr. 5 D-40225 Duesseldorf Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Goebels