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Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis

Copland, D. A., Hussain, K., Baalasubramanian, Sivasankar, Hughes, Timothy Richard, Morgan, Bryan Paul, Xu, H., Dick, A. D. and Nicholson, L. B. 2010. Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis. Clinical and Experimental Immunology 159 (3) , pp. 303-314. 10.1111/j.1365-2249.2009.04070.x

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Abstract

Activation of complement occurs during autoimmune retinal and intraocular inflammatory disease as well as neuroretinal degenerative disorders. The cleavage of C5 into fragments C5a and C5b is a critical event during the complement cascade. C5a is a potent proinflammatory anaphylatoxin capable of inducing cell migration, adhesion and cytokine release, while membrane attack complex C5b-9 causes cell lysis. Therapeutic approaches to prevent complement-induced inflammation include the use of blocking monoclonal antibodies (mAb) to prevent C5 cleavage. In these current experiments, the rat anti-mouse C5 mAb (BB5·1) was utilized to investigate the effects of inhibition of C5 cleavage on disease progression and severity in experimental autoimmune uveoretinitis (EAU), a model of organ-specific autoimmunity in the eye characterized by structural retinal damage mediated by infiltrating macrophages. Systemic treatment with BB5·1 results in significantly reduced disease scores compared with control groups, while local administration results in an earlier resolution of disease. In vitro, contemporaneous C5a and interferon-g signalling enhanced nitric oxide production, accompanied by down-regulation of the inhibitory myeloid CD200 receptor, contributing to cell activation. These experiments demonstrate that C5 cleavage contributes to the full expression of EAU, and that selective C5 blockade via systemic and local routes of administration can suppress disease. This presents great therapeutic potential to protect against tissue damage during autoimmune responses in the retina or inflammation-induced degenerative disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Uncontrolled Keywords: autoimmunity, complement C5, experimental autoimmune uveoretinitis, macrophage activation, therapy
Publisher: Wiley-Blackwell
ISSN: 0009-9104
Last Modified: 04 Jun 2017 03:46
URI: http://orca-mwe.cf.ac.uk/id/eprint/26361

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