Functional characterization and biomarker identification in the Brown Norway model of allergic airway inflammation.
1. The antigen-induced inflammatory response in the Brown Norway rat is a model commonly used to assess the impact of novel compounds on airway eosinophilia. A detailed functional, cellular and molecular characterization of this model has not yet been performed within a single study. This information together with the temporal changes in this phenomenon should be known before this model can be used, with confidence, to elucidate the mechanisms of action of novel anti-inflammatory drugs. 2. Antigen challenge caused an accumulation of eosinophils in lung tissue 24 h after challenge. Accumulation of CD2(+) T cells was not apparent until after 72 h. 3. Interestingly, mRNA for the Th2 type cytokines interleukin (IL)-4, IL-5 and IL-13 and eotaxin were elevated in lung tissue after challenge and the expression of IL-13 and eotaxin protein increased at around 8-12 h. The temporal changes in both the biomarker production and the functional responses are important factors to consider in protocol design prior to initiating a compound screening program. 4. A neutralising antibody (R73) against alphabeta-TCR caused a significant reduction in T cell numbers accompanied by a significant suppression of eosinophil accumulation. 5. Airway hyperreactivity (AHR) was not apparent in this specific Brown Norway model in sensitized animals after a single or multiple challenges although eosinophil influx was seen in the same animals. 6. In conclusion, this is a convenient pre-clinical model (incorporating the measurement of biomarkers and functional responses) for screening novel small molecule inhibitors and/or biotherapeutics targeted against T cell/eosinophil infiltration/activation.
Department of Respiratory Disease, Aventis Pharma, Route 202-206, Bridgewater, New Jersey, NJ 07928, USA.
Stephen L
SL
Underwood
El-Bdaoui
el-B
Haddad
Mark A
MA
Birrell
Kerryn
K
McCluskie
Michaela
M
Pecoraro
Dominika
D
Dabrowski
Stephen E
SE
Webber
Martyn L
ML
Foster
Maria G
MG
Belvisi
D000818:Animals; D015415:Biomarkers; D016535:Bronchial Hyperreactivity; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000209:etiology*; D004804:Eosinophils / Q000502:physiology; D006967:Hypersensitivity / Q000209:etiology*; D007249:Inflammation / Q000209:etiology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology; D013601:T-Lymphocytes
D015415:Biomarkers; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta