Tempero Pharmaceuticals, a GSK Company, USA
Jianfei Yang is a Principal Scientist and a Project Leader of a Th17 cell-related project at Tempero Pharmaceuticals, a GSK company, in Cambridge, MA, USA. He received a Ph.D. in Pathology from Niigata University in Japan in 1997. He then obtained postdoctoral training in Dr. Ken Murphy’s lab at HHMI and Washington University. In the past 16 year, he has been studying the role of CD4+ T helper cells in immunity and diseases. He has more than 10 years of experience in autoimmune disease research and pharmaceutical drug development. He has published numerous papers and patents.
Th17 cells play a critical role in the pathogenesis of autoimmune diseases. Diff erentiation of Th 17 cells requires the nuclear receptor RORt, and inhibition of RORt by small molecule inhibitors prevents Th 17 cell diff erentiation in vitro. RORt inhibitors also modulate RORt activity in vivo as demonstrated by a signifi cant reduction in the severity of experimental autoimmune encephalomyelitis. However, the eff ect of RORt small molecule inhibitors on the in vivo generation of Th 17 cells has not yet been clearly demonstrated. Here we report a novel, potent, and selective RORt inverse agonist TMP778 and demonstrate its role in the in vivo diff erentiation of Th 17 cells. TMP778 blocks both human and mouse Th 17 cell diff erentiation in vitro. In vivo, administration of TMP778 to C57BL/6 mice immunized with myelin oligodendrocyte peptide 35-55 (MOG35- 55) blocked MOG-specifi c IL-17A expression. In addition, expression of Th 17 signature genes (Il17a, Il17f, Il22, and CCL20) as well as Ifn was inhibited. Further, IL-17-producing CD4+ T cells were signifi cantly reduced in IL-17-IRES-GFP transgenic mice administrated TMP778 aft er immunization with MOG35-55. Th us, our studies demonstrate that RORt inverse agonist TMP778 suppress Th 17 diff erentiation in vivo.