Effect of an orally active Th1/Th2 balance modulator, M50367, on IgE production, eosinophilia, and airway hyperresponsiveness in mice.
We have found a novel anti-allergic agent, M50367, which suppresses IgE biosynthesis and eosinophil accumulation in vivo. In this study, we evaluated the ability of M50367 to modulate Th1/Th2 balance in Th2-background BALB/c mice and to inhibit airway hyperresponsiveness in a murine model of atopic asthma. Oral M50367 at 3-30 mg/kg/day exhibited 51 to 73% reduction of IL-4/IL-5 production and 2- to 5-fold augmentation of IFN-gamma production by Ag-stimulated cultured splenocytes of the mice sensitized with DNP-Ascaris. These alterations in Th1/Th2 cytokine production were accompanied by 55-85% suppression of plasma IgE level. Oral M50367 at a dose of 10 mg/kg/day significantly inhibited Ig-independent peritoneal eosinophilia by 54%, which was induced by repeated i.p. injections of Ascaris suum extract. To develop airway hyperresponsiveness caused by allergic airway inflammation, BALB/c mice were sensitized with i.p. OVA injections, followed three times by OVA inhalation. Oral M50367 significantly inhibited the increase in airway reactivity to acetylcholine, together with the elevation of plasma IgE level and pulmonary eosinophilia, which were observed in vehicle-treated mice 1 day after the last inhalation. Moreover, M50367 treatment reduced IL-4 and IL-5 production and tended to enhance IFN-gamma production, not only by cultured splenocytes, but also in bronchoalveolar lavage fluid. These results suggest that M50367 has a modulating ability of Th1/Th2 balance to down-regulate Th2 response in the circulating system as well as at the sites of inflammation, and may be beneficial for the treatment of allergic disorders such as atopic asthma.
Kato
Y
Y
Research Center, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan. yutakato@mochida.co.jp
Manabe
T
T
Tanaka
Y
Y
Mochizuki
H
H
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000918:Antibody Specificity / Q000187:drug effects; D000947:Antigens, Helminth / Q000276:immunology; D017165:Ascaris suum / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology*; D004136:Dinitrobenzenes / Q000276:immunology; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006969:Hypersensitivity, Immediate / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007136:Immunoglobulins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010533:Peritoneal Lavage; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018926:Anti-Allergic Agents; D000947:Antigens, Helminth; D001562:Benzimidazoles; D004136:Dinitrobenzenes; D007136:Immunoglobulins; C119626:M 50367; D007073:Immunoglobulin E