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

Geoffrey A Pietersz, Patricia L Mottram, Nicholas C van de Velde, Caroline Tan Sardjono, Sandra E Esparon, Paul Allen Ramsland, Gerard Moloney, Jonathan Bayldon Baell, Tom D McCarthy, Barry Ross Matthews, Maree Powell, Phillip Mark Hogarth

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Abstract

The interaction of immune complexes with the human Fc receptor, FcI?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 FcI?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 FcI?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 FcI?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 FcI?RIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes.
Original languageEnglish
Pages (from-to)3 - 12
Number of pages10
JournalImmunology and Cell Biology
Volume87
Issue number1
DOIs
Publication statusPublished - 2009
Externally publishedYes

Cite this

Pietersz, Geoffrey A ; Mottram, Patricia L ; van de Velde, Nicholas C ; Sardjono, Caroline Tan ; Esparon, Sandra E ; Ramsland, Paul Allen ; Moloney, Gerard ; Baell, Jonathan Bayldon ; McCarthy, Tom D ; Matthews, Barry Ross ; Powell, Maree ; Hogarth, Phillip Mark. / Inhibition of destructive autoimmune arthritis in FcgRIIa transgenic mice by small chemical entities. In: Immunology and Cell Biology. 2009 ; Vol. 87, No. 1. pp. 3 - 12.
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abstract = "The interaction of immune complexes with the human Fc receptor, FcI?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 FcI?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 FcI?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 FcI?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 FcI?RIIa receptor antagonists demonstrated their potential as anti-inflammatory agents for autoimmune diseases involving immune complexes.",
author = "Pietersz, {Geoffrey A} and Mottram, {Patricia L} and {van de Velde}, {Nicholas C} and Sardjono, {Caroline Tan} and Esparon, {Sandra E} and Ramsland, {Paul Allen} and Gerard Moloney and Baell, {Jonathan Bayldon} and McCarthy, {Tom D} and Matthews, {Barry Ross} and Maree Powell and Hogarth, {Phillip Mark}",
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Pietersz, GA, Mottram, PL, van de Velde, NC, Sardjono, CT, Esparon, SE, Ramsland, PA, Moloney, G, Baell, JB, McCarthy, TD, Matthews, BR, Powell, M & Hogarth, PM 2009, 'Inhibition of destructive autoimmune arthritis in FcgRIIa transgenic mice by small chemical entities', Immunology and Cell Biology, vol. 87, no. 1, pp. 3 - 12. https://doi.org/10.1038/icb.2008.82

Inhibition of destructive autoimmune arthritis in FcgRIIa transgenic mice by small chemical entities. / Pietersz, Geoffrey A; Mottram, Patricia L; van de Velde, Nicholas C; Sardjono, Caroline Tan; Esparon, Sandra E; Ramsland, Paul Allen; Moloney, Gerard; Baell, Jonathan Bayldon; McCarthy, Tom D; Matthews, Barry Ross; Powell, Maree; Hogarth, Phillip Mark.

In: Immunology and Cell Biology, Vol. 87, No. 1, 2009, p. 3 - 12.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Pietersz, Geoffrey A

AU - Mottram, Patricia L

AU - van de Velde, Nicholas C

AU - Sardjono, Caroline Tan

AU - Esparon, Sandra E

AU - Ramsland, Paul Allen

AU - Moloney, Gerard

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AU - Matthews, Barry Ross

AU - Powell, Maree

AU - Hogarth, Phillip Mark

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

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