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

Abstract

<b>Background and Aims:</b> 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. <b>Methods:</b> 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 <i>in vivo</i> was assessed in the CD4⁺CD45RB^high T cell transfer model. <b>Results:</b> 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 <i>CXCL1, CXCL8</i> and <i>CCL20</i>. BI119 significantly reduced <i>IL17</i> and <i>IL26</i> transcription in colonic and ileal CD biopsies and did not affect <i>IL22</i>. BI119 has a more profound effect in ileal CD with additional significant downregulation of <i>IL23R, CSF2, CXCL1, CXCL8</i>, and <i>S100A8</i>, and upregulation of <i>DEFA5</i>. BI119 significantly prevented development of clinical, macroscopic and molecular markers of colitis in the T-cell transfer model. <b>Conclusions:</b> BI119 modulated CD-relevant Th17 signatures, including downregulation of <i>IL23R</i> 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.