Publication Date:
2014-03-08
Description:
IL-17–producing CD4 + Th17 cells, CD8 + Tc17 cells, and T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORt 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 ROR t -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 T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORt 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 RORt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by 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, RORt 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.
Print ISSN:
0022-1767
Electronic ISSN:
1550-6606
Topics:
Medicine
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