title: Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations.
abstract: Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. GeneticRorcdeficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions. In vitro, RORC inhibitors induced apoptosis, as well asBcl2l1andBCL2L1mRNA downregulation, in mouse and nonhuman primate thymocytes, respectively. Chronic, 13-week RORC inhibitor treatment in rats caused progressive thymic alterations in all analyzed rats similar to those inRorc-deficient mice prior to T cell lymphoma development. One rat developed thymic cortical hyperplasia with preneoplastic features, including increased mitosis and reduced IKAROS expression, albeit without skewed T cell clonality. In summary, pharmacological inhibition of RORC not only blocks Th17 cell development and related cytokine production, but also recapitulates thymic aberrations seen inRorc-deficient mice. While RORC inhibition may offer an effective therapeutic principle for Th17-mediated diseases, T cell lymphoma with chronic therapy remains an apparent risk.
authors.affiliation: Autoimmunity, Transplantation, and Inflammation Disease Area.
authors.forename: Christine
authors.initials: C
authors.lastname: Guntermann
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piaia
authors.affiliation: CiToxLAB, Evreux, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Hamel
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Diethilde
authors.initials: D
authors.lastname: Theil
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Rubic-Schneider
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Rio-Espinola
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Dong
authors.affiliation: Autoimmunity, Transplantation, and Inflammation Disease Area.
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
authors.affiliation: Autoimmunity, Transplantation, and Inflammation Disease Area.
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.affiliation: Autoimmunity, Transplantation, and Inflammation Disease Area.
authors.forename: Janet
authors.initials: J
authors.lastname: Dawson
authors.affiliation: Global Discovery Chemistry.
authors.forename: Klemens
authors.initials: K
authors.lastname: Hoegenauer
authors.affiliation: Global Discovery Chemistry.
authors.forename: David
authors.initials: D
authors.lastname: Orain
authors.affiliation: Global Discovery Chemistry.
authors.forename: Samuel
authors.initials: S
authors.lastname: Hintermann
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Rowan
authors.initials: R
authors.lastname: Stringer
authors.affiliation: Autoimmunity, Transplantation, and Inflammation Disease Area.
authors.forename: Dhavalkumar D
authors.initials: DD
authors.lastname: Patel
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Arno
authors.initials: A
authors.lastname: Doelemeyer
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Deurinck
authors.affiliation: Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Schümann
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics; D058504:Th17 Cells / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000473:pathology*
chemical_list: D018168:Receptors, Retinoic Acid