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    Inhibition of destructive autoimmune arthritis in Fc?RIIa transgenic mice by small chemical entities

    Access Status
    Fulltext not available
    Authors
    Pietersz, G.
    Mottram, P.
    Van De Velde, N.
    Sardjono, C.
    Esparon, S.
    Ramsland, Paul
    Moloney, G.
    Baell, J.
    McCarthy, T.
    Matthews, B.
    Powell, M.
    Hogarth, P.
    Date
    2009
    Type
    Journal Article
    
    Metadata
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    Citation
    Pietersz, G. and Mottram, P. and Van De Velde, N. and Sardjono, C. and Esparon, S. and Ramsland, P. and Moloney, G. et al. 2009. Inhibition of destructive autoimmune arthritis in Fc?RIIa transgenic mice by small chemical entities. Immunology and Cell Biology. 87 (1): pp. 3-12.
    Source Title
    Immunology and Cell Biology
    DOI
    10.1038/icb.2008.82
    ISSN
    0818-9641
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/42104
    Collection
    • Curtin Research Publications
    Abstract

    The interaction of immune complexes with the human Fc receptor, Fc?RIIa, initiates the release of inflammatory mediators and is implicated in the pathogenesis of human autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, so this FcR is a potential target for therapy. We have used the three-dimensional structure of an Fc?RIIa dimer to design small molecule inhibitors, modeled on a distinct groove and pocket created by receptor dimerization, adjacent to the ligand-binding sites. These small chemical entities (SCEs) blocked immune complex-induced platelet activation and aggregation and tumor necrosis factor secretion from macrophages in a human cell line and transgenic mouse macrophages. The SCE appeared specific for Fc?RIIa, as they inhibited only immune complex-induced responses and had no effect on responses to stimuli unrelated to FcR, for example platelet stimulation with arachidonic acid. In vivo testing of the SCE in Fc?RIIa transgenic mice showed that they inhibited the development and stopped the progression of collagen-induced arthritis (CIA). The SCEs were more potent than methotrexate and anti-CD3 in sustained suppression of CIA. Thus, in vitro and in vivo activity of these SCE Fc?RIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes. © 2009 Australasian Society for Immunology Inc. All rights reserved.

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