Publications & Reports

Inhibition of destructive autoimmune arthritis in FcgammaRIIa transgenic mice by small chemical entities.

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
Centre for Immunology, Burnet Institute at Austin, Heidelberg, Victoria, Australia. gpietersz@burnet.edu.au

Abstract

The interaction of immune complexes with the human Fc receptor, FcgammaRIIa, 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 FcgammaRIIa 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 FcgammaRIIa, 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 FcgammaRIIa 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 FcgammaRIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes.

Projects

  • Characterising the cause of human inflammation in autoimmune disease using transgenic mouse models
    Antibodies activate and modulate normal immunity but in certain inflammatory conditions (especially autoimmunity), antibodies trigger destructive information through Fc receptors and in particular through the FcgRIIa. By blocking this receptor, destructive inflammation can be completely inhibited. This has broad implications for other related diseases including lupus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, vitiligo and vasculitis, including Wegener's granulomatosis.
  • New approaches to the treatment of lupus
    Lupus is a neglected severe chronic disease primarily affecting women. We discover the receptor that triggers inflammation caused by immune complexes (ab and antibodies produced in lupus and related diseases like rheumatoid arthritis). Antiphospholipid syndrome a particular complication of lupus but one also found in the broader community also involves immune complex activation of life-threatening blood clotting. We are researching potential new diagnostic and therapeutic approaches targeting the cause of the disease.

Publication

  • Journal: Immunology and Cell Biology
  • Published: 01/01/2009
  • Volume: 87
  • Issue: 1
  • Pagination: 3-12

Authors