Effect of topical immunomodulators on acute allergic inflammation and bronchial hyperresponsiveness in sensitised rats.
We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.
Huang
Tung Jung
TJ
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK.
Eynott
Paul
P
Salmon
Michael
M
Nicklin
Paul L
PL
Chung
K Fan
KF
D000109:Acetylcholine / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D001993:Bronchodilator Agents / Q000494:pharmacology; D019819:Budesonide / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014665:Vasodilator Agents / Q000494:pharmacology
D001993:Bronchodilator Agents; D003524:Cyclosporins; D016207:Cytokines; C082770:IMM 125; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D014665:Vasodilator Agents; D019819:Budesonide; D010047:Ovalbumin; D000109:Acetylcholine; D020123:Sirolimus