AUTHOR=Bassolas-Molina Helena , Raymond Ernest , Labadia Mark , Wahle Joseph , Ferrer-Picón Elena , Panzenbeck Mark , Zheng Jie , Harcken Christian , Hughes Robert , Turner Michael , Smith Dustin , Calderón-Gómez Elisabeth , Esteller Míriam , Carrasco Anna , Esteve Maria , Dotti Isabella , Corraliza Ana Maria , Masamunt Maria Carme , Arajol Clàudia , Guardiola Jordi , Ricart Elena , Nabozny Gerald , Salas Azucena 

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

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02307

DOI=10.3389/fimmu.2018.02307

ISSN=1664-3224

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