{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:43:25Z","timestamp":1793375005417,"version":"4.5.0"},"reference-count":36,"publisher":"American Society for Clinical Investigation","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,3,9]]},"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>","DOI":"10.1172\/jci.insight.91127","type":"journal-article","created":{"date-parts":[[2017,3,8]],"date-time":"2017-03-08T11:01:03Z","timestamp":1488970863000},"source":"Crossref","is-referenced-by-count":58,"title":["Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations"],"prefix":"10.1172","volume":"2","author":[{"given":"Christine","family":"Guntermann","sequence":"first","affiliation":[{"name":"Autoimmunity, Transplantation, and Inflammation Disease Area,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Piaia","sequence":"additional","affiliation":[{"name":"Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, 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