Combined sensitization of mice to extracts of dust mite, ragweed, and Aspergillus species breaks through tolerance and establishes chronic features of asthma.
BACKGROUND
Existing asthma models develop tolerance when chronically exposed to the same allergen.


OBJECTIVE
We sought to establish a chronic model that sustains features of asthma long after discontinuation of allergen exposure.


METHODS
We immunized and exposed mice to a combination of single, double, or triple allergens (dust mite, ragweed, and Aspergillus species) intranasally for 8 weeks. Airway hyperreactivity (AHR) and morphologic features of asthma were studied 3 weeks after allergen exposure. Signaling effects of the allergens were studied on dendritic cells.


RESULTS
Sensitization and repeated exposure to a single allergen induced tolerance. Sensitization to double and especially triple allergens broke through tolerance and established AHR, eosinophilic inflammation, mast cell and smooth muscle hyperplasia, mucus production, and airway remodeling that persisted at least 3 weeks after allergen exposure. Mucosal exposure to triple allergens in the absence of an adjuvant was sufficient to induce chronic airway inflammation. Anti-IL-5 and anti-IL-13 antibodies inhibited inflammation and AHR in the acute asthma model but not in the chronic triple-allergen model. Multiple allergens produce a synergy in p38 mitogen-activated protein kinase signaling and maturation of dendritic cells, which provides heightened T-cell costimulation at a level that cannot be achieved with a single allergen.


CONCLUSIONS
Sensitivity to multiple allergens leads to chronic asthma in mice. Multiple allergens synergize in dendritic cell signaling and T-cell stimulation that allows escape from the single allergen-associated tolerance development.
Department of Medicine, Division of Allergy and Immunology, National Jewish Health, University of Colorado Denver Health Sciences Center, Denver, CO 80206, USA.
Nicholas
N
Goplen
M Zunayet
MZ
Karim
Qiaoling
Q
Liang
Magdalena M
MM
Gorska
Sadee
S
Rozario
Lei
L
Guo
Rafeul
R
Alam
D000485:Allergens / Q000276:immunology*; D031164:Ambrosia / Q000276:immunology*; D000818:Animals; D001230:Aspergillus / Q000276:immunology*; D001249:Asthma / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000209:etiology; D018925:Chemokines / Q000032:analysis; D002908:Chronic Disease; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D007108:Immune Tolerance; D007114:Immunization; D007073:Immunoglobulin E / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D039981:Pyroglyphidae / Q000276:immunology*
D000485:Allergens; D018925:Chemokines; D016207:Cytokines; D007073:Immunoglobulin E; D010047:Ovalbumin; D048049:Extracellular Signal-Regulated MAP Kinases