Inhibitors of RORγt Targeting Th17 Cells May Hold Promising Therapeutic Potential in Inflammation & Autoimmunity
Recently, several RORγt inhibitors have been identified that effectively restrict the function and differentiation of pro-inflammatory T helper (Th)17 cells.
The transcription factor RORγt belongs to the nuclear receptor superfamily – consisting of 48 members that serve as ligand-activated transcription factors translating extracellular or intracellular signals into a transcriptional response. RORγt is the immune cell-specific isoform of RORγ (retinoic acid receptor-related orphan nuclear receptor gamma), and has garnered considerable interest because it represents the master transcription factor essential for the development of Th17cells (I Ivanov et al, Cell, 2006, 126:1121; L Klotz & Knolle P, FEBS Lett, 2011, 585:3764; JR Huh & Littman DR, Eur J Immunol, 2012, 42:2232).
The Th17cells, discovered in 2005, are now considered as key players in the pathogenesis of numerous inflammatory/autoimmune diseases, including rheumatoid arthritis, Guillain-Barré syndrome, Takayasu arteritis, and perhaps atherosclerosis and fibromyalgia.
Along these lines, the recently developed small molecule inhibitors of RORγt may represent a promising therapeutic target in many inflammatory/autoimmune disorders. It remains to be seen whether these inhibitors will be effective in clinical applications and settings (JR Huh & Littman DR, Eur J Immunol, 2012, 42:2232; F Isono, S Fujita-Sato & Ito S, Drug Discov Today, 2014, 19:1205).
Recently, Lead Pharma, a company focused on the development of small molecule drugs, announced that it has achieved the first milestone under its research collaboration with Sanofi. The collaboration includes the development of small molecules targeting the transcription factor RORγt, aimed at the treatment of a broad range of autoimmune disorders.
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