YM-341619 suppresses the differentiation of spleen T cells into Th2 cells in vitro, eosinophilia, and airway hyperresponsiveness in rat allergic models.
T helper (Th) 2 cells play a central role in the pathogenesis of allergic diseases such as allergic asthma, atopic dermatitis, and allergic rhinitis. We have found that YM-341619 hydrochloride, which suppressed IL-4-induced STAT6-dependent reporter gene expression, inhibited the differentiation of mouse spleen T cells into Th2 cells in vitro. YM-341619 suppressed the production of IL-4 and the expression of GATA-3 mRNA, a Th2 transcription factor, in T cells cultured with anti-CD3 antibody and anti-CD28 antibody in the presence of IL-4. In contrast, the production of IFN-gamma and the expression of T-bet mRNA, a Th1 transcription factor, in T cells cultured with anti-CD3 antibody in the presence of IL-12, were not effected by YM-341619. Orally administered YM-341619 (0.003-0.03 mg/kg) reduced the plasma IgE level of DNP-Ascaris-sensitized rats, but not the IgG(2a) level. YM-341619 suppressed IL-4 and IL-13 production in the splenocytes of these DNP-Ascaris-sensitized rats without augmenting IFN-gamma production. YM-341619 also dose-dependently suppressed eosinophil accumulation in the lung (0.003-3 mg/kg, p.o.) and airway hyperresponsiveness (0.3-3 mg/kg, p.o.) induced by repeated exposure to ovalbumin in ovalbumin-sensitized rats. These results suggest that YM-341619 has the ability to suppress allergen-induced Th2 responses by selectively inhibiting the differentiation of CD4(+) T cells into the Th2 subset.
Ohga
Keiko
K
Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. keiko.ohga@jp.astellas.com
Kuromitsu
Sadao
S
Takezawa
Ryuichi
R
Numazaki
Mako
M
Ishikawa
Jun
J
Nagashima
Shinya
S
Shimizu
Yasuaki
Y
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000188:drug therapy*; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D050800:STAT6 Transcription Factor / Q000235:genetics; D013154:Spleen / Q000166:cytology*; D013601:T-Lymphocytes / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology*
C532176:2-((4-morpholin-4-ylphenyl)amino)-4-((2,3,6-trifluorobenzyl)amino)pyrimidine-5-carboxamide; D050990:GATA3 Transcription Factor; D009025:Morpholines; D011743:Pyrimidines; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma