PMID- 27844029
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 2328-9503 (Print)
IS  - 2328-9503 (Electronic)
IS  - 2328-9503 (Linking)
VI  - 3
IP  - 11
DP  - 2016 Nov
TI  - Dose-dependent inhibition of demyelination and microglia activation by IVIG.
PG  - 828-843
AB  - OBJECTIVE: 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 an ex vivo model of 
      the central nervous system (CNS)-immune interface. METHODS: 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. RESULTS: 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. 
      INTERPRETATION: 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.
FAU - Winter, Meike
AU  - Winter M
AD  - Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf 
      Moorenstr. 5 D-40225 Duesseldorf Germany.
FAU - Baksmeier, Christine
AU  - Baksmeier C
AD  - Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf 
      Moorenstr. 5 D-40225 Duesseldorf Germany.
FAU - Steckel, Julia
AU  - Steckel J
AD  - Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf 
      Moorenstr. 5 D-40225 Duesseldorf Germany.
FAU - Barman, Sumanta
AU  - Barman S
AD  - Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf 
      Moorenstr. 5 D-40225 Duesseldorf Germany.
FAU - Malviya, Manish
AU  - Malviya M
AD  - 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-Universite 
      Toulouse III Toulouse France.
FAU - Harrer-Kuster, Melanie
AU  - Harrer-Kuster M
AD  - University of Zuerich, Clinical Neuroimmunology Zuerich Switzerland; Present 
      address: Abb Vie AG Baar Switzerland.
FAU - Hartung, Hans-Peter
AU  - Hartung HP
AD  - Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf 
      Moorenstr. 5 D-40225 Duesseldorf Germany.
FAU - Goebels, Norbert
AU  - Goebels N
AD  - Department of Neurology, Medical Faculty Heinrich-Heine-University Duesseldorf 
      Moorenstr. 5 D-40225 Duesseldorf Germany.
LA  - eng
PT  - Journal Article
DEP - 20160923
PL  - United States
TA  - Ann Clin Transl Neurol
JT  - Annals of clinical and translational neurology
JID - 101623278
PMC - PMC5099529
EDAT- 2016/11/16 06:00
MHDA- 2016/11/16 06:01
PMCR- 2016/09/23
CRDT- 2016/11/16 06:00
PHST- 2015/08/13 00:00 [received]
PHST- 2016/04/25 00:00 [revised]
PHST- 2016/05/09 00:00 [accepted]
PHST- 2016/11/16 06:00 [entrez]
PHST- 2016/11/16 06:00 [pubmed]
PHST- 2016/11/16 06:01 [medline]
PHST- 2016/09/23 00:00 [pmc-release]
AID - ACN3326 [pii]
AID - 10.1002/acn3.326 [doi]
PST - epublish
SO  - Ann Clin Transl Neurol. 2016 Sep 23;3(11):828-843. doi: 10.1002/acn3.326. 
      eCollection 2016 Nov.