TU-572, a potent and selective CD45 inhibitor, suppresses IgE-mediated anaphylaxis and murine contact hypersensitivity reactions.
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.


METHODS
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.


CONCLUSIONS
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.
Hamaguchi
T
T
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan. tak.hamaguchi@po.rd.taisho.co.jp
Takahashi
A
A
Manaka
A
A
Sato
M
M
Osada
H
H
D000707:Anaphylaxis / Q000188:drug therapy*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D003877:Dermatitis, Contact / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006636:Histamine Release; D006969:Hypersensitivity, Immediate / Q000188:drug therapy; D017493:Leukocyte Common Antigens / Q000187:drug effects*; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010853:Picryl Chloride / Q000009:adverse effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013454:Sulfoxides / Q000494:pharmacology* / Q000627:therapeutic use
C419888:2-((4-methylthiopyridin-2-yl)methylsulfinyl)benzimidazole; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D013454:Sulfoxides; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases; D010853:Picryl Chloride