Inhibition of destructive autoimmune arthritis in Fc gamma RIIa transgenic mice by small chemical entities
- Author(s)
- Pietersz, GA; Mottram, PL; de Velde, NCV; Sardjono, CT; Esparon, S; Ramsland, PA; Moloney, G; Baell, JB; McCarthy, TD; Matthews, BR; Powell, MS; Hogarth, PM;
- Details
- Publication Year 2009-01,Volume 87,Issue #1,Page 3-12
- Journal Title
- IMMUNOLOGY AND CELL BIOLOGY
- Publication Type
- Journal Article
- Abstract
- The interaction of immune complexes with the human Fc receptor, Fc gamma 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 gamma 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 gamma 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 gamma 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 gamma RIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes.
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- COLLAGEN-INDUCED ARTHRITIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; LOW-AFFINITY RECEPTOR; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODIES; IMMUNE-COMPLEXES; DISEASE; INFLAMMATION; BINDING; CLEARANCE
- Publisher's Version
- https://doi.org/10.1038/icb.2008.82
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- Refer to copyright notice on published article.
Creation Date: 2009-01-01 12:00:00