Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model

Halstead, S., Zitman, F., Humphreys, P., Greenshields, K., Verschuuren, J., Jacobs, B., Rother, R., Plomp, J. and Willison, H. (2008) Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model. Brain, 131(5), pp. 1197-1208. (doi:10.1093/brain/awm316)

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Abstract

Anti-GQ1b ganglioside antibodies are the serological hallmark of the Miller Fisher syndrome (MFS) variant of the paralytic neuropathy, Guillain–Barré syndrome, and are believed to be the principal pathogenic mediators of the disease. In support of this, we previously showed in an in vitro mouse model of MFS that anti-GQ1b antibodies were able to bind and disrupt presynaptic motor nerve terminals at the neuromuscular junction (NMJ) as one of their target sites, thereby causing muscle paralysis. This injury only occurred through activation of complement, culminating in the formation and deposition of membrane attack complex (MAC, C5b-9) in nerve membranes. Since this step is crucial to the neuropathic process and an important convergence point for antibody and complement mediated membrane injury in general, it forms an attractive pharmacotherapeutic target. Here, we assessed the efficacy of the humanized monoclonal antibody eculizumab, which blocks the formation of human C5a and C5b-9, in preventing the immune-mediated motor neuropathy exemplified in this model. Eculizumab completely prevented electrophysiological and structural lesions at anti-GQ1b antibody pre-incubated NMJs in vitro when using normal human serum (NHS) as a complement source. In a novel in vivo mouse model of MFS generated through intraperitoneal injection of anti-GQ1b antibody and NHS, mice developed respiratory paralysis due to transmission block at diaphragm NMJs, resulting from anti-GQ1b antibody binding and complement activation. Intravenous injection of eculizumab effectively prevented respiratory paralysis and associated functional and morphological hallmarks of terminal motor neuropathy. We show that eculizumab protects against complement-mediated damage in murine MFS, providing the rationale for undertaking clinical trials in this disease and other antibody-mediated neuropathies in which complement activation is believed to be involved.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Willison, Professor Hugh and Greenshields, Dr Kay
Authors: Halstead, S., Zitman, F., Humphreys, P., Greenshields, K., Verschuuren, J., Jacobs, B., Rother, R., Plomp, J., and Willison, H.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Brain
ISSN:0006-8950
Published Online:08 January 2008

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
402991An integrated approach to novel mechanisms and therapeutic strategies in murine models of human autoimmune neuropathyHugh WillisonWellcome Trust (WELLCOME)077041/Z/05/ZInfection Immunity and Inflammation Medicine