1. An RORγt oral inhibitor modulates IL-17 responses in peripheral blood and intestinal mucosa of Crohn's disease patients
- Author
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Helena Bassolas-Molina, Ernest Raymond, Mark Labadia, Joseph Wahle, Elena Ferrer-Picón, Mark Panzenbeck, Jie Zheng, Christian Harcken, Robert Hughes, Michael Turner, Dustin Smith, Elisabeth Calderón-Gómez, Míriam Esteller, Anna Carrasco, Maria Esteve, Isabella Dotti, Ana Maria Corraliza, Maria Carme Masamunt, Clàudia Arajol, Jordi Guardiola, Elena Ricart, Gerald Nabozny, Azucena Salas, and Universitat de Barcelona
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,T cell ,Biopsy ,Immunology ,T cells ,Antígens ,commensal antigens ,Peripheral blood mononuclear cell ,Interleukin 22 ,T-cell-transfer ,03 medical and health sciences ,Mice ,Intestinal mucosa ,Downregulation and upregulation ,Crohn Disease ,Malaltia de Crohn ,RAR-related orphan receptor gamma ,T-Lymphocyte Subsets ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Colitis ,Intestinal Mucosa ,Antigens ,Original Research ,Inhibition ,business.industry ,Interleukin-17 ,RORγt inhibition ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,medicine.disease ,Disease Models, Animal ,Crohn's disease ,030104 developmental biology ,medicine.anatomical_structure ,Cèl·lules T ,Inhibició ,Leukocytes, Mononuclear ,Cytokines ,Th17 Cells ,Interleukin 17 ,Th17 ,Inflammation Mediators ,business ,lcsh:RC581-607 ,Biomarkers - Abstract
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+CD45RBhigh 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.