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| Título: | Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. |
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| Autor/a: | 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. |
| Otros autores: | Universitat de Barcelona |
| 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. |
| Materia(s): | Artritis Proteïnes Psoriasi Farmacologia Arthritis Proteins Psoriasis Pharmacology |
| Derechos: | cc-by (c) Xue et al., 2016
http://creativecommons.org/licenses/by/3.0/es |
| Tipo de documento: | Artículo info:eu-repo/semantics/publishedVersion |
| Editor: | Nature Publishing Group |
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