Format

Send to

Choose Destination
J Dermatol Sci. 2017 Jan;85(1):12-19. doi: 10.1016/j.jdermsci.2016.10.001. Epub 2016 Oct 3.

Oral administration of a novel RORγt antagonist attenuates psoriasis-like skin lesion of two independent mouse models through neutralization of IL-17.

Author information

1
Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
2
Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
3
Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
4
Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan. Electronic address: sano.derma@kochi-u.ac.jp.

Abstract

BACKGROUND:

Targeting the IL-17 pathway represents a highly effective strategy for the treatment of psoriasis, using antibodies against IL-17A and IL-17 receptor, suggesting that Th17 cells essentially contribute to development of psoriasis. Th17 differentiation depends on the key transcription factor, RORγt.

OBJECTIVE:

To develop a novel RORγt antagonist which is effective on psoriasis via oral administration.

METHODS:

A chemical library was screened using cell-based high-throughput methods, luciferase reporter assay, competitive binding assay, and T cell differentiation assay. To evaluate in vivo effects of a novel RORγt antagonist, A213, we orally administrated it to two independent mouse models of psoriasis; IL-23-injection model and K5.Stat3C transgenic mouse.

RESULTS:

Oral administration of A213 resulted in attenuation of skin inflammation in the both mouse models. At the same time, increased levels of IL-17A expression were significantly reduced in the skin lesions and skin-draining lymph nodes.

CONCLUSION:

These results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis.

KEYWORDS:

Antagonist; Mouse model; Psoriasis; RORγt; Th17

PMID:
27726924
DOI:
10.1016/j.jdermsci.2016.10.001
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center