Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica. (1st May 2018)

• Record Type: Journal Article
• Authors: Tradtrantip, Lukmanee; Felix, Christian M.; Spirig, Rolf; Morelli, Adriana Baz; Verkman, A.S.
• Is Part Of: Neuropharmacology. Volume 133(2018)
• Page Start: 345
• Page End: 353
• Publication Date: 2018-05-01
• Subjects: AQP4 -- NMO -- Fc multimer -- Astrocyte -- Complement -- Immunoglobulin -- Neuroinflammation; ADCC antibody-dependent cellular cytotoxicity -- AQP4 aquaporin-4 -- AQP4-IgG neuromyelitis optica immunoglobulin G antibody -- BSA bovine serum albumin -- CDC complement-dependent cytotoxicity -- GFAP glial fibrillary acidic protein -- ITP idiopathic thrombocytopenic purpura -- IVIG intravenous immunoglobulin -- MAC membrane attack complex -- MBP myelin basic protein -- NK cell natural killer cell -- NMO neuromyelitis optica spectrum disorders -- PFA paraformaldehyde; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.02.002
• Languages: English
• ISSNs: 0028-3908

Abstract

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 50 mg/kg taken at 8 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 50 mg/kg administered before and at 12 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. Highlights: Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system. Recombinant Fc hexamers, consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1, were studied for treatment of NMO. Fc hexamers inhibited complement- and cell-mediated cytotoxicity caused by NMO autoantibody in vitro and prevented NMO pathology in a rat model of NMO.