A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations

Autor: Michitaka Shichijo, Azumi Ueyama, Masaya Shimizu, Kazufumi Katayama, Takayuki Okuno, Yoshikazu Sasaki, Chihiro Imura, Kenichiro Tsujii, Yoko Furue, Kiyoshi Yasui, Nobuyuki Tai, Mina Yamamoto
Rok vydání: 2018
Předmět:
0301 basic medicine
T cell
Primary Cell Culture
Drug Evaluation
Preclinical
Mice
Transgenic
Dermatology
Administration
Cutaneous
Biochemistry
Severity of Illness Index
030207 dermatology & venereal diseases
03 medical and health sciences
Mice
0302 clinical medicine
RAR-related orphan receptor gamma
Psoriasis
medicine
Animals
Humans
Sulfones
Molecular Biology
Cells
Cultured
Thymic Lymphoma
Skin
business.industry
Innate lymphoid cell
Interleukin-17
Interleukin
T-Lymphocytes
Helper-Inducer
Nuclear Receptor Subfamily 1
Group F
Member 3
medicine.disease
Healthy Volunteers
Immunity
Innate
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Treatment Outcome
Cancer research
Leukocytes
Mononuclear
Tetradecanoylphorbol Acetate
Interleukin 17
Dermatologic Agents
business
CD8
Zdroj: Journal of dermatological science. 93(3)
ISSN: 1873-569X
Popis: Background Retinoic acid receptor-related orphan receptor gamma t (RORγt) has critical roles in the development, maintenance and function of interleukin (IL)-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune disease, particularly psoriasis. On the other hand, RORγt is also critical for controlling apoptosis during thymopoiesis, and genetic RORγt ablation or systematic RORγt inhibition cause progressive thymic aberrations leading to T cell lymphomas. Objective We investigated whether topical administration of our novel RORγt inhibitor, S18-000003 has therapeutic potential for psoriasis with low risk of thymic aberrations. Methods We evaluated the effect of topical S18-000003 on psoriasis-like skin inflammation and influence on the thymus in a 12-O-tetradecanoylphorbol-13-acetate-induced K14.Stat3C mouse psoriasis model. Results S18-000003 markedly inhibited the development of psoriatic skin inflammation via suppression of the IL-17 pathway. In the skin, S18-000003 suppressed all subsets of IL-17-producing cells that we previously identified in this psoriasis model: Th17 cells, Tc17 cells, dermal γδ T cells, TCR− cells that probably included innate lymphoid cells, and CD4−CD8− double-negative αβ T cells. Notably, neither reduction of CD4+CD8+ double-positive thymocytes nor dysregulation of cell cycling was observed in S18-000003-treated mice, even at a high dose. Conclusion Our topically administered RORγt inhibitor is a potential therapeutic agent for psoriasis with low risk of thymic lymphoma.
Databáze: OpenAIRE
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