RATIONALE: In humans, immune responses to inhaled aeroallergens develop in the lung and draining lymph nodes. Many animal models of asthma bypass this route, and instead employ intra-peritoneal injections of allergen using alum as an adjuvant. OBJECTIVES: We investigated whether allergic sensitization through the airway elicits immune responses qualitatively different than those arising in the peritoneum. METHODS: Mice were sensitized through the airway using low dose lipopolysaccharide as an adjuvant, or through the peritoneum using alum as an adjuvant. After a single allergen challenge, ELISA and flow cytometry were used to measure cytokines and leukocyte subsets. Invasive measurements of airway resistance were used to measure allergen-induced airway hyperreactivity. RESULTS: Sensitization through the peritoneum primed strong Th2 responses and eosinophilia, but not AHR, after a single allergen challenge. By contrast, allergic sensitization through the airway primed only modest Th2 responses, but strong Th17 responses. Th17 cells homed to the lung and released IL-17 into the airway upon subsequent encounter with inhaled allergen. As a result, these mice developed IL-17-dependent airway neutrophilia and AHR. This AHR was neutrophil-dependent because it was abrogated in CXCR2-deficient mice and also in wild type mice receiving a neutrophil-depleting antibody. Individually, neither IL-17 nor ongoing Th2 responses were sufficient to confer AHR, but together acted synergistically to promote neutrophil recruitment, eosinophil recruitment and AHR. CONCLUSIONS: Allergic sensitization through the airway primes modest Th2 responses, but strong Th17 responses that promote airway neutrophilia and acute AHR. These findings support a causal role for neutrophils in severe asthma.
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