TU-572, a Potent and Selective CD45 Inhibitor, Suppresses IgE-Mediated Anaphylaxis and Murine Contact Hypersensitivity Reactions

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.

Inhibition of CD45 Phosphatase Activity Induces Cell Cycle Arrest and Apoptosis of CD45+ Lymphoid Tumors Ex Vivo and In Vivo

“…Antibodies directed to the extracellular domain of CD45 have been used for cancer management (Hamaguchi et al, 2001;Nemecek and Matthews, 2002;Pagel et al, 2003). One problem with the use of anti-CD45 mAbs is that these agents target all cells expressing CD45 (normal resting and rapidly proliferating lymphoid cells), regardless of whether CD45 is functionally essential to that cell.…”

“…To control the growth of leukemias and lymphomas, antibodies directed to the extracellular domain of CD45 have been used to eliminate CD45 1 cells but have had limited clinical efficacy (Hamaguchi et al, 2001;Nemecek and Matthews, 2002;Pagel et al, 2003). One problem is that anti-CD45 monoclonal antibodies (mAb) target all CD45 1 cells, regardless of whether CD45 activity is functionally essential to that cell.…”

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

“…Competitive CD45 inhibitors that block substrates from docking (Beers et al, 1997) and substrate analogs that poison the catalytic pocket have been reported (Urbanek et al, 2001), with an in vitro IC 50 value of approximately 0.2 mM and activity in antiproliferative assays. One competitive inhibitor (a benzimidazole derivative) had effects on histamine release from rat peritoneal mast cells (Hamaguchi et al, 2001). Unfortunately, these CD45 inhibitors are not clinically useful.…”

4‐Isoavenaciolide covalently binds and inhibits VHR, a dual‐specificity phosphatase

“…Protein phosphatase inhibitors are useful tools to reveal signal transduction pathways of immune response as well as to cure immunological diseases [27,28]. In this report, we identified 4‐iA as a potent VHR inhibitor and investigated the effect of 4‐iA on VHR, a well‐characterized member of DSPases.…”