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http://hdl.handle.net/2445/116509
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DC Field | Value | Language |
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dc.contributor.author | Xue, Xiaohua | - |
dc.contributor.author | Soroosh, Pejman | - |
dc.contributor.author | De Leon-Tabaldo, Aimee | - |
dc.contributor.author | Luna-Roman, Rosa | - |
dc.contributor.author | Sablad, Marciano | - |
dc.contributor.author | Rozenkrants, Natasha | - |
dc.contributor.author | Yu, Jingxue | - |
dc.contributor.author | Castro, Glenda | - |
dc.contributor.author | Banie, Homayon | - |
dc.contributor.author | Fung-Leung, Wai-Ping | - |
dc.contributor.author | Santamaria Babí, Luis F. | - |
dc.contributor.author | Schlueter, Thomas | - |
dc.contributor.author | Albers, Michael | - |
dc.contributor.author | Leonard, Kristi | - |
dc.contributor.author | Budelsky, Alison L. | - |
dc.contributor.author | Fourie, Anne M. | - |
dc.date.accessioned | 2017-10-11T14:35:53Z | - |
dc.date.available | 2017-10-11T14:35:53Z | - |
dc.date.issued | 2016-12-01 | - |
dc.identifier.issn | 2045-2322 | - |
dc.identifier.uri | http://hdl.handle.net/2445/116509 | - |
dc.description.abstract | The IL-23/IL-17 pathway is implicated in autoimmune diseases, particularly psoriasis, where biologics targeting IL-23 and IL-17 have shown significant clinical efficacy. Retinoid-related orphan nuclear receptor gamma t (RORγt) is required for Th17 differentiation and IL-17 production in adaptive and innate immune cells. We identified JNJ-54271074, a potent and highly-selective RORγt inverse agonist, which dose-dependently inhibited RORγt-driven transcription, decreased co-activator binding and promoted interaction with co-repressor protein. This compound selectively blocked Th17 differentiation, significantly reduced IL-17A production from memory T cells, and decreased IL-17A- and IL-22-producing human and murine γδ and NKT cells. In a murine collagen-induced arthritis model, JNJ-54271074 dose-dependently suppressed joint inflammation. Furthermore, JNJ-54271074 suppressed IL-17A production in human PBMC from rheumatoid arthritis patients. RORγt-deficient mice showed decreased IL-23-induced psoriasis-like skin inflammation and cytokine gene expression, consistent with dose-dependent inhibition in wild-type mice through oral dosing of JNJ-54271074. In a translational model of human psoriatic epidermal cells and skin-homing T cells, JNJ-54271074 selectively inhibited streptococcus extract-induced IL-17A and IL-17F. JNJ-54271074 is thus a potent, selective RORγt modulator with therapeutic potential in IL-23/IL-17 mediated autoimmune diseases. | - |
dc.format.extent | 17 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Nature Publishing Group | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1038/srep37977 | - |
dc.relation.ispartof | Scientific Reports, 2016, vol. 6, p. 37977 | - |
dc.relation.uri | https://doi.org/10.1038/srep37977 | - |
dc.rights | cc-by (c) Xue et al., 2016 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es | - |
dc.source | Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) | - |
dc.subject.classification | Artritis | - |
dc.subject.classification | Proteïnes | - |
dc.subject.classification | Psoriasi | - |
dc.subject.classification | Farmacologia | - |
dc.subject.other | Arthritis | - |
dc.subject.other | Proteins | - |
dc.subject.other | Psoriasis | - |
dc.subject.other | Pharmacology | - |
dc.title | Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 667799 | - |
dc.date.updated | 2017-10-11T14:35:54Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 27905482 | - |
Appears in Collections: | Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) |
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667799.pdf | 2.69 MB | Adobe PDF | View/Open |
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