PMID- 33880776 OWN - NLM STAT- MEDLINE DCOM- 20211005 LR - 20231107 IS - 1365-2567 (Electronic) IS - 0019-2805 (Print) IS - 0019-2805 (Linking) VI - 164 IP - 1 DP - 2021 Sep TI - Modified recombinant human IgG1-Fc is superior to natural intravenous immunoglobulin at inhibiting immune-mediated demyelination. PG - 90-105 LID - 10.1111/imm.13341 [doi] AB - Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Although Fc fragments derived from IVIG have shown efficacy in controlling immune thrombocytopenia in children, the mechanisms of action are unclear and controversial. The aim of this study was to dissect IVIG effector mechanisms using further adapted Fc fragments on demyelination in an ex vivo model of the central nervous system-immune interface. Using organotypic cerebellar slice cultures (OSCs) from transgenic mice, we induced extensive immune-mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective effects of adapted Fc fragments were assessed by live imaging of green fluorescent protein expression, immunohistochemistry and confocal microscopy. Cysteine- and glycan-adapted Fc fragments protected OSC from demyelination in a dose-dependent manner where equimolar concentrations of either IVIG or control Fc were ineffective. The protective effects of the adapted Fc fragments are partly attributed to interference with complement-mediated oligodendroglia damage. Transcriptome analysis ruled out signatures associated with inflammatory or innate immune responses. Taken together, our findings show that recombinant biomimetics can be made that are at least two hundred-fold more effective than IVIG in controlling demyelination by anti-MOG antibodies. CI - (c) 2021 The Authors. Immunology published by John Wiley & Sons Ltd. FAU - Baksmeier, Christine AU - Baksmeier C AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. FAU - Blundell, Pat AU - Blundell P AD - Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK. FAU - Steckel, Julia AU - Steckel J AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. FAU - Schultz, Verena AU - Schultz V AD - Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. FAU - Gu, Quan AU - Gu Q AD - Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. FAU - Da Silva Filipe, Ana AU - Da Silva Filipe A AD - Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. FAU - Kohl, Alain AU - Kohl A AD - Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. FAU - Linnington, Chris AU - Linnington C AD - Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. FAU - Lu, Dongli AU - Lu D AD - Department of Life Sciences, Imperial College London, London, UK. FAU - Dell, Anne AU - Dell A AD - Department of Life Sciences, Imperial College London, London, UK. FAU - Haslam, Stuart AU - Haslam S AD - Department of Life Sciences, Imperial College London, London, UK. FAU - Wang, Jiabin AU - Wang J AD - Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. FAU - Czajkowsky, Dan AU - Czajkowsky D AD - State Key Laboratory for Oncogenes and Related Genes and Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. FAU - Goebels, Norbert AU - Goebels N AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany. FAU - Pleass, Richard J AU - Pleass RJ AUID- ORCID: 0000-0001-7438-8296 AD - Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK. LA - eng GR - BB/F008309/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom GR - 208938/Z/17/Z/WT_/Wellcome Trust/United Kingdom GR - MC_UU_12014/12/MRC_/Medical Research Council/United Kingdom GR - 2017-18 MM9MC_PC_17167/MRC_/Medical Research Council/United Kingdom GR - MC_UU_12014/8/MRC_/Medical Research Council/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - MC_PC_17167/MRC_/Medical Research Council/United Kingdom PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210509 PL - England TA - Immunology JT - Immunology JID - 0374672 RN - 0 (Autoantibodies) RN - 0 (Immunoglobulin Fc Fragments) RN - 0 (Immunoglobulin G) RN - 0 (Immunoglobulins, Intravenous) RN - 0 (Myelin-Oligodendrocyte Glycoprotein) RN - 0 (Recombinant Fusion Proteins) SB - IM MH - Animals MH - Autoantibodies/genetics/*therapeutic use MH - Cerebellum/drug effects/*pathology MH - Demyelinating Diseases/immunology/*therapy MH - HEK293 Cells MH - Humans MH - Immunoglobulin Fc Fragments/genetics/*therapeutic use MH - Immunoglobulin G/genetics/*therapeutic use MH - Immunoglobulins, Intravenous/therapeutic use MH - Mice MH - Mice, Inbred C57BL MH - Myelin-Oligodendrocyte Glycoprotein/immunology MH - Oligodendroglia/drug effects/*pathology MH - Organ Culture Techniques MH - Recombinant Fusion Proteins/genetics/*therapeutic use PMC - PMC8358725 OTO - NOTNLM OT - Fc monomers OT - Fc multimers OT - IgG OT - demyelination OT - immunoglobulin OT - intravenous immunoglobulin COIS- The patent describing the original hexamers is assigned to CSL Behring Lengnau AG. R.J.P. and P.A.B. declare that the molecules discussed within are subject to ongoing patent applications. The other authors have no financial conflicts of interest. EDAT- 2021/04/22 06:00 MHDA- 2021/10/06 06:00 PMCR- 2021/05/09 CRDT- 2021/04/21 06:58 PHST- 2021/03/23 00:00 [revised] PHST- 2021/01/22 00:00 [received] PHST- 2021/03/31 00:00 [accepted] PHST- 2021/04/22 06:00 [pubmed] PHST- 2021/10/06 06:00 [medline] PHST- 2021/04/21 06:58 [entrez] PHST- 2021/05/09 00:00 [pmc-release] AID - IMM13341 [pii] AID - 10.1111/imm.13341 [doi] PST - ppublish SO - Immunology. 2021 Sep;164(1):90-105. doi: 10.1111/imm.13341. Epub 2021 May 9.