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 28, 2017
Citation Information: JCI Insight. 2017;2(5):e91127. doi:10.1172/jci.insight.91127.
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Categories: 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 5

Histopathological analysis of thymic alterations in rats treated with retinoic-acid-orphan-receptor-C (RORC) inhibitor cpd 1 for 13 weeks compared with vehicle control.

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Histopathological analysis of thymic alterations in rats treated with re...
(A) Subgross view of H&E-stained sections of thymus from vehicle- (left) or cpd 1–treated (right) rats. Cpd 1–induced increase in thymic cortical/medullary ratio (scale bar: 200 μm). (B) Higher magnification showing the cpd 1–induced increase of relative presence of larger thymocytes in cpd 1–treated (right) compared with vehicle-treated (left) rat (scale bar: 40 μm). (C) H&E-stained section of thymus from cpd 1–treated rat showing cortical lymphoid hyperplasia. Subgross view revealed that the normal cortico-medullary demarcation was focally lost (left, scale bar: 200 μm) and a monomorphic population of large round cells was present (right, scale bar: 50 μm). (D) IKAROS expression in thymus from vehicle- (left) or cpd 1–treated rat showing cortical lymphoid hyperplasia (middle and right). IKAROS expression was reduced in the cortical hyperplastic area. Black arrowheads point to cortical-medullary demarcation, red arrowheads point to lymphoid cells that lost IKAROS, and arrows point to unstained epitheloid cell. n = 9–10.