T Hamaguchi1, A Takahashi, A Manaka, M Sato, H Osada. 1. Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan. tak.hamaguchi@po.rd.taisho.co.jp
Abstract
BACKGROUND: CD45, receptor-type protein tyrosine phosphatases (PTPases) are essential components of signaling through both the T cell receptor and the B cell antigen receptor. However, the functional significance of CD45 in the signaling pathway through the high-affinity immunoglobulin (Ig) E receptor has not yet been established. In this study, we demonstrate that the potent CD45 inhibitor negatively regulates IgE-dependent anaphylaxis and contact hypersensitivity reactions. METHOD: We have previously found that TU-572, 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]-5-isopropoxybenzimidazole, had a potent and selective inhibitory effect against PTPase activity of CD45. Using a CD45 inhibitor, we examined in vitro and in vivo IgE-mediated responses. RESULTS: TU-572 potently inhibited histamine release from rat peritoneal mast cells and mouse systemic anaphylaxis reaction using monoclonal anti-dinitrophenyl (DNP) IgE and DNP-BSA. TU-572 also suppressed the immediate-type hypersensitivity response induced by repeated epicutaneous application of trinitrochlorobenzene in BALB/c mice. CONCLUSION: These findings revealed that the PTPase activity of CD45 played a critical role in signal transduction of IgE-mediated anaphylaxis in vitro and in vivo. PTPase inhibitors such as TU-572 are useful in the treatment of allergic diseases. Copyright 2002 S. Karger AG, Basel
BACKGROUND:CD45, receptor-type protein tyrosine phosphatases (PTPases) are essential components of signaling through both the T cell receptor and the B cell antigen receptor. However, the functional significance of CD45 in the signaling pathway through the high-affinity immunoglobulin (Ig) E receptor has not yet been established. In this study, we demonstrate that the potent CD45 inhibitor negatively regulates IgE-dependent anaphylaxis and contact hypersensitivity reactions. METHOD: We have previously found that TU-572, 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]-5-isopropoxybenzimidazole, had a potent and selective inhibitory effect against PTPase activity of CD45. Using a CD45 inhibitor, we examined in vitro and in vivo IgE-mediated responses. RESULTS:TU-572 potently inhibited histamine release from rat peritoneal mast cells and mouse systemic anaphylaxis reaction using monoclonal anti-dinitrophenyl (DNP) IgE and DNP-BSA. TU-572 also suppressed the immediate-type hypersensitivity response induced by repeated epicutaneous application of trinitrochlorobenzene in BALB/c mice. CONCLUSION: These findings revealed that the PTPase activity of CD45 played a critical role in signal transduction of IgE-mediated anaphylaxis in vitro and in vivo. PTPase inhibitors such as TU-572 are useful in the treatment of allergic diseases. Copyright 2002 S. Karger AG, Basel