Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/116509
Title: | Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. |
Author: | Xue, Xiaohua Soroosh, Pejman De Leon-Tabaldo, Aimee Luna-Roman, Rosa Sablad, Marciano Rozenkrants, Natasha Yu, Jingxue Castro, Glenda Banie, Homayon Fung-Leung, Wai-Ping Santamaria Babí, Luis F. Schlueter, Thomas Albers, Michael Leonard, Kristi Budelsky, Alison L. Fourie, Anne M. |
Keywords: | Artritis Proteïnes Psoriasi Farmacologia Arthritis Proteins Psoriasis Pharmacology |
Issue Date: | 1-Dec-2016 |
Publisher: | Nature Publishing Group |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/srep37977 |
It is part of: | Scientific Reports, 2016, vol. 6, p. 37977 |
URI: | http://hdl.handle.net/2445/116509 |
Related resource: | https://doi.org/10.1038/srep37977 |
ISSN: | 2045-2322 |
Appears in Collections: | Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) |
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