Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8517042 | Neuropharmacology | 2018 | 26 Pages |
Abstract
Intravenous human immunoglobulin G (IVIG) may have therapeutic benefit in neuromyelitis optica spectrum disorders (herein called NMO), in part because of the anti-inflammatory properties of the IgG Fc region. Here, we evaluated recombinant Fc hexamers consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1. In vitro, the Fc hexamers prevented cytotoxicity in aquaporin-4 (AQP4) expressing cells and in rat spinal cord slice cultures exposed to NMO anti-AQP4 autoantibody (AQP4-IgG) and complement, with >500-fold greater potency than IVIG or monomeric Fc fragments. Fc hexamers at low concentration also prevented antibody-dependent cellular cytotoxicity produced by AQP4-IgG and natural killer cells. Serum from rats administered a single intravenous dose of Fc hexamers at 50â¯mg/kg taken at 8â¯h did not produce complement-dependent cytotoxicity when added to AQP4-IgG-treated AQP4-expressing cell cultures. In an experimental rat model of NMO produced by intracerebral injection of AQP4-IgG, Fc hexamers at 50â¯mg/kg administered before and at 12â¯h after AQP4-IgG fully prevented astrocyte injury, complement activation, inflammation and demyelination. These results support the potential therapeutic utility of recombinant IgG1 Fc hexamers in AQP4-IgG seropositive NMO.
Keywords
Aquaporin-4AQP4-IgGNMOIVIgADCCAQP4PFACDCMBPGFAPBSAAstrocytebovine serum albuminantibody-dependent cellular cytotoxicityNeuromyelitis optica spectrum disordersNeuroinflammationimmunoglobulin Intravenous immunoglobulinNK cellNatural killer cellcomplement-dependent cytotoxicityComplementMACITPparaformaldehydeidiopathic thrombocytopenic purpuraGlial fibrillary acidic proteinMyelin basic proteinmembrane attack complex
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Authors
Lukmanee Tradtrantip, Christian M. Felix, Rolf Spirig, Adriana Baz Morelli, A.S. Verkman,