Small Molecule Inhibitors Targeting the Th17 Cell Transcription Factor RORγt for the Treatment of Autoimmune Diseases

Abstract

Naïve CD4 + T helper cells can differentiate into Th1, Th2, Th17, T regulatory, Th9 and Th22 cells. Th1 cells are characterized by their production of IFNγ but not IL-4 and IL-5 while Th2 cells are characterized by their expression of IL-4 and IL-5 but not IFNγ. T-bet and GATA3 are the master transcription factors for Th1 and Th2 cells, respectively [1]. Th1 cells mediate cellular immunity against intracellular pathogens while Th2 cells induce humoral immunity to parasitic helminthes. Th1/Th2 cells are believed to play an important role in several types of autoimmune diseases. Th9 cells produce IL-9 that has been associated with a variety of inflammatory diseases. Th22 cells, which express IL-22 only, may mediate both protective immunity and inflammation. T regulatory cells, which are characterized by CD25 and the master transcription factor Foxp3, play critical role in regulation of overactive immune systems. Th17 cells, which are characterized by the expression of IL-17A, IL-17F,IL-22, IL-23R and CCR6, have been shown to play a critical role in a variety of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease (IBD), and asthma as well as in tumor immunity [2,3]. Th17 cells express two IL-17 family members, namely IL-17A and IL-17F. Both cytokines signal through the same receptors, IL-17RA and IL-17RC. IL-17A can be detected in sera of asthmatic patients and synovial fluids of arthritic patients. Suppression of allergic cellular and humoral responses was observed in IL-17A-deficient mice [4]. In addition, IL-17A-deficient mice are protected from collagen-induced arthritis (CIA) [5] and treatment with neutralizing anti-mouse IL-17A antibody after the onset of CIA significantly reduced the severity of CIA [6]. Fully human monoclonal antibodies targeting IL-17A and the IL-17RA have shown clinical efficacy in psoriasis, rheumatoid arthritis, and uveitis [7-9]. Naïve CD4