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Background and Aims:  Despite the negative results of blocking IL-17 in Crohn's disease (CD) patients, selective modulation of Th17-dependent responses warrants further study. Inhibition of retinoic acid-related orphan receptor gamma (RORγt), the master regulator of the Th17 signature, is currently being explored in inflammatory diseases. Our aim was to determine the effect of a novel oral RORγt antagonist (BI119) in human CD and on an experimental model of intestinal inflammation.   Methods:  51 CD patients and 11 healthy subjects were included. The effects of BI119 were tested on microbial-stimulated peripheral blood mononuclear cells (PBMCs), intestinal crypts and biopsies from CD patients. The ability of BI119 to prevent colitis  in vivo  was assessed in the CD4 + CD45RB high  T cell transfer model.   Results:  In bacterial antigen-stimulated PBMCs from CD patients, BI119 inhibits Th17-related genes and proteins, while upregulating Treg and preserving Th1 and Th2 signatures. Intestinal crypts cultured with supernatants from BI119-treated commensal-specific CD4 +  T cells showed decreased expression of  CXCL1, CXCL8  and  CCL20 . BI119 significantly reduced  IL17  and  IL26  transcription in colonic and ileal CD biopsies and did not affect  IL22 . BI119 has a more profound effect in ileal CD with additional significant downregulation of  IL23R, CSF2, CXCL1, CXCL8 , and  S100A8 , and upregulation of  DEFA5 . BI119 significantly prevented development of clinical, macroscopic and molecular markers of colitis in the T-cell transfer model.   Conclusions:  BI119 modulated CD-relevant Th17 signatures, including downregulation of  IL23R  while preserving mucosa-associated IL-22 responses, and abrogated experimental colitis. Our results provide support to the use of RORγt antagonists as a novel therapy to CD treatment.

An RORγt Oral Inhibitor Modulates IL-17 Responses in Peripheral Blood and Intestinal Mucosa of Crohn's Disease Patients