Characterization of YM-58483/BTP2, a novel store-operated Ca super(2+) entry blocker, on T cell-mediated immune responses in vivo

• Published in: International immunopharmacology 2008-12, Vol.8 (13-14), p.1787-1792
• Main Authors: Ohga, Keiko, Takezawa, Ryuichi, Arakida, Yasuhito, Shimizu, Yasuaki, Ishikawa, Jun
• Format: Article
• Language: English
• ISSN: 1567-5769
• DOI: 10.1016/j.intimp.2008.08.016

YM-58483/BTP2 is a blocker of store-operated Ca super(2+) entry (SOCE), which regulates the activation of non-excitable cells such as lymphocytes. YM-58483 has been reported to inhibit cytokine production and proliferation in T cells, and to be useful as a probable medicinal candidate for treatment of bronchial asthma. The present study investigated the pharmacological profile and therapeutic potential of YM-58483 in relation to cell-mediated immune responses. In the mouse graft-versus-host disease (GVHD) model, YM-58483 (1- 30 mg/kg, p.o.) and cyclosporine A (1-30 mg/kg, p.o.) inhibited donor anti- host cytotoxic T lymphocyte (CTL) activity and IFN- gamma production, and also reduced the number of donor T cells, especially donor CD8 super(+) T cells, in the spleen. YM-58483 and cyclosporine A inhibited T cell proliferation in a one-way mixed lymphocyte reaction (MLR) with IC sub(50) values of 330 and 12.7 nM, respectively. Additionally, YM-58483 (1-10 mg/kg, p.o.) and cyclosporine A (2, 10 mg/kg, p.o.) inhibited the sheep red blood cell (SRBC)-induced delayed type hypersensitivity (DTH) response. These results suggest that the inhibition of SOCE leads to the prevention of antigen-induced T cell responses, which participate in autoimmune diseases such as autoimmune hepatitis and rheumatoid arthritis.