{"doi":"10.1172/jci.insight.91127","title":"Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations","abstract":"<jats:p>\n                    Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic\n                    <jats:italic>Rorc</jats:italic>\n                    deficiency 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 as\n                    <jats:italic>Bcl2l1</jats:italic>\n                    and\n                    <jats:italic>BCL2L1</jats:italic>\n                    mRNA 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 in\n                    <jats:italic>Rorc</jats:italic>\n                    -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 in\n                    <jats:italic>Rorc</jats:italic>\n                    -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.\n                  </jats:p>","journal":"JCI Insight","year":2017,"id":608706,"datarank":0.611630616585858,"base_score":4.07753744390572,"endowment":4.07753744390572,"self_citation_contribution":0.611630616585858,"citation_network_contribution":0.0,"self_endowment_contribution":0.611630616585858,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":58,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1563666,"name":"Alessandro Piaia","orcid":null,"position":1,"is_corresponding":false},{"id":1563667,"name":"Marie-Laure Hamel","orcid":null,"position":2,"is_corresponding":false},{"id":1563668,"name":"Diethilde Theil","orcid":null,"position":3,"is_corresponding":false},{"id":1417863,"name":"Tina Rubic-Schneider","orcid":"0000-0001-6704-3783","position":4,"is_corresponding":false},{"id":1563669,"name":"Alberto del Rio-Espinola","orcid":null,"position":5,"is_corresponding":false},{"id":1563670,"name":"Linda Dong","orcid":null,"position":6,"is_corresponding":false},{"id":1563671,"name":"Andreas Billich","orcid":null,"position":7,"is_corresponding":false},{"id":1563672,"name":"Klemens Kaupmann","orcid":null,"position":8,"is_corresponding":false},{"id":1563673,"name":"Janet Dawson","orcid":null,"position":9,"is_corresponding":false},{"id":1563674,"name":"Klemens Hoegenauer","orcid":null,"position":10,"is_corresponding":false},{"id":1563675,"name":"David Orain","orcid":null,"position":11,"is_corresponding":false},{"id":1563676,"name":"Samuel Hintermann","orcid":null,"position":12,"is_corresponding":false},{"id":1563677,"name":"Rowan Stringer","orcid":null,"position":13,"is_corresponding":false},{"id":598553,"name":"Dhavalkumar D. Patel","orcid":"0000-0002-6066-9844","position":14,"is_corresponding":false},{"id":1018228,"name":"Arno Doelemeyer","orcid":"0000-0003-1471-6459","position":15,"is_corresponding":false},{"id":1563678,"name":"Mark Deurinck","orcid":null,"position":16,"is_corresponding":false},{"id":1563679,"name":"Jens Schümann","orcid":null,"position":17,"is_corresponding":false},{"id":1563665,"name":"Christine Guntermann","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations","abstract":"<jats:p>\n                    Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic\n                    <jats:italic>Rorc</jats:italic>\n                    deficiency 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 as\n                    <jats:italic>Bcl2l1</jats:italic>\n                    and\n                    <jats:italic>BCL2L1</jats:italic>\n                    mRNA 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 in\n                    <jats:italic>Rorc</jats:italic>\n                    -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 in\n                    <jats:italic>Rorc</jats:italic>\n                    -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.\n                  </jats:p>","is_dataset_classified":null,"base_score":4.07753744390572,"endowment":4.07753744390572,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28289717","pmcid":"PMC5333964","openalex_id":"https://openalex.org/W2593499442","authors":[],"funders":[],"total_grants":0,"fwci":2.6487,"citation_percentile":0.9021707,"influential_citations":0,"citation_trend":[{"year":2017,"count":3},{"year":2018,"count":6},{"year":2019,"count":10},{"year":2020,"count":5},{"year":2021,"count":14},{"year":2022,"count":2},{"year":2023,"count":6},{"year":2024,"count":6},{"year":2025,"count":4},{"year":2026,"count":2}],"oa_status":"gold","license":null,"oa_locations":[{"url":"http://insight.jci.org/articles/view/91127/files/pdf","host_type":"journal"},{"url":"http://insight.jci.org/articles/view/91127/files/pdf","host_type":"publisher"},{"url":"https://insight.jci.org/articles/view/91127/files/pdf","host_type":"publisher"},{"url":"https://doi.org/10.1172/jci.insight.91127","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28289717","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5333964","host_type":"repository"}],"fields_of_study":["Psoriasis: Treatment and Pathogenesis","T-cell and B-cell Immunology","Immunotherapy and Immune Responses"],"mesh_terms":["Animals","Female","Humans","Male","Mice, Inbred C57BL","Rats, Inbred Lew","Thymus Gland","Down-Regulation","Gene Expression","Rats, Sprague-Dawley","Receptors, Retinoic Acid","Jurkat Cells","Mice","Rats","Th17 Cells"],"keywords":["RAR-related orphan receptor gamma","Orphan receptor","Retinoic acid","Cancer research","Biology","Downregulation and upregulation","Autoimmunity","Nuclear receptor","Immunology","Medicine","Internal medicine","FOXP3","Cell culture","Transcription factor","Immune system","Biochemistry","Genetics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-30T20:36:46.623220Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}