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Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations
Christine Guntermann, … , Mark Deurinck, Jens Schümann
Christine Guntermann, … , Mark Deurinck, Jens Schümann
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e91127. https://doi.org/10.1172/jci.insight.91127.
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Research Article Immunology

Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

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Abstract

Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc 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 Bcl2l1 and BCL2L1 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 Rorc-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 Rorc-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

Christine Guntermann, Alessandro Piaia, Marie-Laure Hamel, Diethilde Theil, Tina Rubic-Schneider, Alberto del Rio-Espinola, Linda Dong, Andreas Billich, Klemens Kaupmann, Janet Dawson, Klemens Hoegenauer, David Orain, Samuel Hintermann, Rowan Stringer, Dhavalkumar D. Patel, Arno Doelemeyer, Mark Deurinck, Jens Schümann

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Figure 7

Inhibition of retinoic-acid-orphan-receptor-C (RORC) accelerates spontaneous apoptosis in mouse and cynomolgus monkey thymocytes in vitro.

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Inhibition of retinoic-acid-orphan-receptor-C (RORC) accelerates spontan...
Freshly isolated thymocytes from C57BL/6 mice (A and C) or cynomolgus monkey (B and D) were cultured either without addition of compound or in the presence of RORC inhibitors or dexamethasone for up to 18 hours. (A and B) At different time intervals, cells were analyzed for Annexin V binding by flow cytometry. The percentage of CD4+CD8+ double-positive thymocytes that underwent apoptosis induced by the RORC inhibitors was calculated and plotted. (C and D) Following 3 and 6 hours incubation time, cells were analyzed for (C) Bcl2l1 or (D) BCL2L1 mRNA expression by qPCR. Representative examples of (C) triplicate readings from 3 mice or (D) triplicate readings of assay duplicates from 1 cynomolgus monkey are shown. Individual data and means ± SD are depicted. *P < 0.05; **P < 0.01; ****P < 0.0001; Dunnett’s test.

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