title: Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo.
abstract: IL-17-producing CD4(+)Th17 cells, CD8(+)Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23-induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8(+) Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23-induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.
authors: Tempero Pharmaceuticals, GlaxoSmithKline, Cambridge, MA 02139;
authors: Jill
authors: J
authors: Skepner
authors: Radha
authors: R
authors: Ramesh
authors: Mark
authors: M
authors: Trocha
authors: Darby
authors: D
authors: Schmidt
authors: Erkan
authors: E
authors: Baloglu
authors: Mercedes
authors: M
authors: Lobera
authors: Thaddeus
authors: T
authors: Carlson
authors: Jonathan
authors: J
authors: Hill
authors: Lisa A
authors: LA
authors: Orband-Miller
authors: Ashley
authors: A
authors: Barnes
authors: Mohamed
authors: M
authors: Boudjelal
authors: Mark
authors: M
authors: Sundrud
authors: Shomir
authors: S
authors: Ghosh
authors: Jianfei
authors: J
authors: Yang
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011565:Psoriasis / Q000097:blood / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects* / Q000276:immunology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054852:Small Molecule Libraries; C588348:TMP778