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

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 4

Impaired methylated BSA–induced (mBSA-induced) delayed-type hypersensitivity (DTH) responses in female Lewis rats by the retinoic-acid-orphan-receptor-C (RORC) inhibitor cpd 1.

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Impaired methylated BSA–induced (mBSA-induced) delayed-type hypersensiti...
Rats were immunized with mBSA/CFA. Two weeks later, the right ears of the animals were challenged with mBSA, while the left ears were treated with vehicle (5% glucose). Immediately prior to challenge, bis in die (b.i.d.) dosing of cpd 1 was started at the indicated doses and continued until the end of the studies. (A) Ear swelling was monitored for 48 hours. An IL-17A–specific antibody (10 mg/kg s.c. dosed 1 day before mBSA challenge) was used as a reference in another group of rats. The mean ± SEM of the thickness ratios between mBSA-challenged and vehicle-treated ears are shown (n = 5). Cpd 1 blood concentration 2 hours after the last dosing was 334 and 1,286 nM at 3 and 10 mg/kg b.i.d., respectively. (B and C) Draining lymph node cells were prepared 48 hours after mBSA challenge and stimulated ex vivo with mBSA. (B) IL-17A concentration in supernatants and (C) frequencies of IL-17A–secreting cells were quantified by ELISA and ELISpot after 72 and 24 hours, respectively. Individual data and mean ± SEM are depicted (n = 4–5). Cpd 1 concentrations in the draining lymph nodes 2 hours after the last dosing were 104, 353, and 1,054 nM at 0.3, 1, and 3 mg/kg b.i.d., respectively. *P < 0.05; **P < 0.01; Dunnett’s test.