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Life Sci. 2017 Dec 15;191:166-174. doi: 10.1016/j.lfs.2017.10.029. Epub 2017 Oct 19.

JTE-852, a novel spleen tyrosine kinase inhibitor, blocks immunoglobulin G-mediated cellular responses and autoimmune reactions in vivo.

Author information

1
Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. Electronic address: toshinobu.kato@jt.com.
2
Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.

Abstract

AIMS:

Immune and inflammatory responses mediated by immunoglobulin (Ig) G are largely responsible for the pathogenesis of autoimmune diseases. Spleen tyrosine kinase (Syk) plays a pivotal role in the IgG-mediated responses; therefore, Syk has emerged as a new therapeutic target for the treatment of autoimmune diseases. In this study, we investigated the inhibitory actions of JTE-852, a novel Syk inhibitor, on IgG-mediated cellular responses and autoimmune reactions in vivo.

MAIN METHODS:

We examined mediator secretion from human monocytes. We also conducted rat models of reversed cutaneous anaphylaxis (RCA) and reversed passive Arthus (RPA), which are classified as type II and type III hypersensitivities, respectively. In a rat collagen-induced arthritis (CIA) model, JTE-852 or methotrexate was administered preventively (before the onset of arthritis) or therapeutically (after the onset of arthritis).

KEY FINDINGS:

JTE-852 blocked secretion of reactive oxygen species and tumor necrosis factor-α from monocytes stimulated by IgG crosslinking. In the RCA and RPA models, JTE-852 also suppressed edema and dye leakage, respectively. In the CIA model, JTE-852 showed both preventive and therapeutic effects against joint swelling and bone erosion; on the other hand, methotrexate did not show the therapeutic effect.

SIGNIFICANCE:

JTE-852 attenuates IgG-mediated responses and signs in animal model of autoimmune diseases. JTE-852 is thus a promising candidate for a novel, orally available drug for the treatment of autoimmune diseases.

KEYWORDS:

Animal model; Autoimmune disease; IgG; JTE-852; Spleen tyrosine kinase

PMID:
29056373
DOI:
10.1016/j.lfs.2017.10.029
[Indexed for MEDLINE]

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