Inhibition of destructive autoimmune arthritis in FcgammaRIIa transgenic mice by small chemical entities.
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.
Pietersz
Geoffrey A
GA
Centre for Immunology, Burnet Institute at Austin, Heidelberg, Victoria, Australia. gpietersz@burnet.edu.au
Mottram
Patricia L
PL
van de Velde
Nicholas C
NC
Sardjono
Caroline Tan
CT
Esparon
Sandra
S
Ramsland
Paul A
PA
Moloney
Gerard
G
Baell
Jonathan B
JB
McCarthy
Tom D
TD
Matthews
Barry R
BR
Powell
Maree S
MS
Hogarth
P Mark
PM
D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015539:Platelet Activation / Q000187:drug effects / Q000276:immunology; D011487:Protein Conformation; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D020298:U937 Cells
D018501:Antirheumatic Agents; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha