JTE-852, a novel spleen tyrosine kinase inhibitor, blocks immunoglobulin G-mediated cellular responses and autoimmune reactions in vivo
T Kato, T Ohta, H Iwasaki, H Kobayashi, A Matsuo… - Life sciences, 2017 - Elsevier
T Kato, T Ohta, H Iwasaki, H Kobayashi, A Matsuo, T Hata, M Matsushita
Life sciences, 2017•ElsevierAims 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 …
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 …
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.
Elsevier