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

Guntermann, Christine and Piaia, Alessandro and Hamel, Marie-Laure and Theil, Diethilde and Rubic-Schneider, Tina and Del Rio Espinola, Alberto and Dong, Linda and Billich, Andreas and Kaupmann, Klemens and Dawson King, Janet and Hoegenauer, Klemens and Orain, David and Hintermann, Samuel and Stringer, Rowan and Patel, Dhavalkumar and Doelemeyer, Arno and Deurinck, Mark and Schuemann, Jens (2017) Retinoic-acid-orphan-receptor C inhibition suppresses Th17 cells and induces thymic aberrations. The Journal of Clinical Investigation Insight (JCI Insight).

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.

Item Type: Article
Date Deposited: 02 Jun 2017 00:45
Last Modified: 02 Jun 2017 00:45
URI: https://oak.novartis.com/id/eprint/30892

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