ORIGINAL RESEARCH published: 22 October 2018 doi: 10.3389/fimmu.2018.02307 Frontiers in Immunology | www.frontiersin.org 1 October 2018 | Volume 9 | Article 2307 Edited by: Philippe Saas, INSERM U1098 Interactions Hôte-Greffon-Tumeur Ingénierie Cellulaire et Génique, France Reviewed by: Mathieu Uzzan, Mount Sinai Medical Center, United States Megan K. Levings, University of British Columbia, Canada *Correspondence: Azucena Salas asalas1@clinic.ub.es Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology Received: 05 July 2018 Accepted: 17 September 2018 Published: 22 October 2018 Citation: Bassolas-Molina H, Raymond E, Labadia M, Wahle J, Ferrer-Picón E, Panzenbeck M, Zheng J, Harcken C, Hughes R, Turner M, Smith D, Calderón-Gómez E, Esteller M, Carrasco A, Esteve M, Dotti I, Corraliza AM, Masamunt MC, Arajol C, Guardiola J, Ricart E, Nabozny G and Salas A (2018) An RORγ t Oral Inhibitor Modulates IL-17 Responses in Peripheral Blood and Intestinal Mucosa of Crohn’s Disease Patients. Front. Immunol. 9:2307. doi: 10.3389/fimmu.2018.02307 An RORγt Oral Inhibitor Modulates IL-17 Responses in Peripheral Blood and Intestinal Mucosa of Crohn’s Disease Patients Helena Bassolas-Molina 1 , Ernest Raymond 2 , Mark Labadia 2 , Joseph Wahle 2 , Elena Ferrer-Picón 1 , Mark Panzenbeck 2 , Jie Zheng 2 , Christian Harcken 2 , Robert Hughes 3 , Michael Turner 3 , Dustin Smith 3 , Elisabeth Calderón-Gómez 1 , Míriam Esteller 1 , Anna Carrasco 4,5 , Maria Esteve 4,5 , Isabella Dotti 1 , Ana Maria Corraliza 1 , Maria Carme Masamunt 1 , Clàudia Arajol 6 , Jordi Guardiola 6 , Elena Ricart 1 , Gerald Nabozny 2 and Azucena Salas 1 * 1 Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain, 2 Department of Immunology and Respiratory, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States, 3 Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United States, 4 Department of Gastroenterology, Hospital Universitari Mutua Terrassa, Barcelona, Spain, 5 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain, 6 Department of Gastroenterology, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain 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.