Baksmeier, C. et al. (2021) Modified recombinant human IgG1-Fc is superior to natural intravenous immunoglobulin at inhibiting immune-mediated demyelination. Immunology, 164(1), pp. 90-105. (doi: 10.1111/imm.13341) (PMID:33880776) (PMCID:PMC8358725)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by an Innovator Grant from the Wellcome Trust to RP and NG (208938/Z/17/Z) and an institutional MRC Confidence in Concepts award 2017-18 MM9 MC_PC_17167; and also by the Biotechnology and Biological Sciences Research Council grant BBF0083091 (A. Dell and S.M. Haslam), MRC MC UU 12014/8 and MC UU 12014/12 (A. Kohl and Q. Gu, A. Filipe. respectively) and by grants (31670722, 31971151 and 81627801) from the National Science Foundation of China (D.M.C). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Linington, Professor Christopher and Schultz, Dr Verena and Gu, Dr Quan and Da Silva Filipe, Dr Ana and Kohl, Professor Alain |
| Authors: | Baksmeier, C., Blundell, P., Steckel, J., Schultz, V., Gu, Q., Da Silva Filipe, A., Kohl, A., Linnington, C., Lu, D., Dell, A., Haslam, S., Wang, J., Czajkowsky, D., Goebels, N., and Pleass, R. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
| Journal Name: | Immunology |
| Publisher: | Wiley |
| ISSN: | 0019-2805 |
| ISSN (Online): | 1365-2567 |
| Published Online: | 20 April 2021 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in Immunology 164(1): 90-105 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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