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TMP778, a selective inhibitor of RORγt, suppresses experimental autoimmune uveitis development, but affects both Th17 and Th1 cell populations
Author(s) -
Lyu Cancan,
Bing So Jin,
Wandu Wambui S.,
Xu Biying,
Shi Guangpu,
Hinshaw Samuel J.,
Lobera Mercedes,
Caspi Rachel R.,
Lu Lin,
Yang Jianfei,
Gery Igal
Publication year - 2018
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201747029
Subject(s) - rar related orphan receptor gamma , biology , autoimmunity , immune system , immunology , uveitis , t cell , retinoid , transcription factor , foxp3 , microbiology and biotechnology , cell culture , gene , retinoic acid , genetics
Abstract Experimental autoimmune uveitis (EAU), an animal model for severe intraocular inflammatory eye diseases, is mediated by both Th1 and Th17 cells. Here, we examined the capacity of TMP778, a selective inhibitor of RORγt, to inhibit the development of EAU, as well as the related immune responses. EAU was induced in B10.A mice by immunization with interphotoreceptor retinoid‐binding protein (IRBP). Treatment with TMP778 significantly inhibited the development of EAU, determined by histological examination. In addition, the treatment suppressed the cellular immune response to IRBP, determined by reduced production of IL‐17 and IFN‐γ, as well as lower percentages of lymphocytes expressing these cytokines, as compared to vehicle‐treated controls. The inhibition of IFN‐γ expression by TMP778 is unexpected in view of this compound being a selective inhibitor of RORγt. The observation was further confirmed by the finding of reduced expression of the T‐bet (Tbx21) gene, the transcription factor for IFN‐γ, by cells of TMP778‐treated mice. Thus, these data demonstrate the capacity of TMP778 to inhibit pathogenic autoimmunity in the eye and shed new light on its mode of action in vivo.