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Abstract
Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system in which binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) to astrocytes causes complement-dependent cytotoxicity (CDC) and inflammation resulting in oligodendrocyte and neuronal injury. There is compelling evidence for a central role of complement in NMO pathogenesis. Here, we evaluated the potential of C1-esterase inhibitor (C1-inh) for complement-targeted therapy of NMO. C1-inh is an anti-inflammatory plasma protein with serine protease inhibition activity that has a broad range of biological activities on the contact (kallikrein), coagulation, fibrinolytic and complement systems. C1-inh is approved for therapy of hereditary angioedema (HAE) and has been studied in a small safety trial in acute NMO relapses (NCT 01759602). In vitro assays of NMO-IgG-dependent CDC showed C1-inh inhibition of human and rat complement, but with predicted minimal complement inhibition activity at a dose of 2000 units in humans. Inhibition of complement by C1-inh was potentiated by ∼10-fold by polysulfated macromolecules including heparin and dextran sulfate. In rats, intravenous C1-inh at a dose 30-fold greater than that approved to treat HAE inhibited serum complement activity by <5%, even when supplemented with heparin. Also, high-dose C1-inh did not reduce pathology in a rat model of NMO produced by intracerebral injection of NMO-IgG. Therefore, although C1r and C1s are targets of C1-inh, our in vitro data with human serum and in vivo data in rats suggest that the complement inhibition activity of C1-inh in serum is too low to confer clinical benefit in NMO.
Highlights
Neuromyelitis optica (NMO) is autoimmune disease of the central nervous system in which inflammatory demyelinating lesions cause optic neuritis and transverse myelitis [1], [2]
The complement system is an attractive target for therapy of NMO, as complement-dependent astrocyte cytotoxicity is an early initiating event in the neuroinflammation and demyelination that occurs in NMO
Selective inhibition of early steps in the classical complement pathway is of particular interest because NMO pathogenesis involves NMO-IgG complement effector function in which the antibody Fc region binds C1q to initiate complement activation
Summary
Neuromyelitis optica (NMO) is autoimmune disease of the central nervous system in which inflammatory demyelinating lesions cause optic neuritis and transverse myelitis [1], [2]. Most NMO patients are seropositive for immunoglobulin G autoantibodies (NMO-IgG) against aquaporin-4 [3], [4], a water channel expressed on the plasma membrane of astrocytes [5]. NMO pathogenesis in patients seropositive for NMO-IgG involves NMO-IgG binding to astrocyte AQP4, causing cytotoxicity with secondary inflammation, oligodendrocyte injury and demyelination [6], [7]. Used NMO therapies include immunosuppressives, B-cell depletion and plasma exchange [8]–[10]. Addition of NMO-IgG and complement to AQP4-expressing cells, including astrocytes, produces complement-dependent cytotoxicity (CDC) [14]–[17].
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