BACKGROUND: Ragweed (Ambrosia artemisiifolia) is a strong elicitor of allergic airway inflammation with worldwide increasing prevalence. Various components of ragweed pollen are thought to play a role in the development of allergic responses. Aim of the study was to identify critical factors for allergenicity of ragweed pollen in a physiologic model of allergic airway inflammation METHODS: Aqueous ragweed pollen extract, the low molecular weight fraction or the major allergen Amb a 1 were instilled intranasally on 1 - 11 consecutive days and allergic airway inflammation was evaluated by bronchoalveolar lavage, lung histology, serology, gene-expression in lung tissue and measurement of lung function. Pollen-derived adenosine was removed from the extract enzymatically in order to analyze its role in ragweed-induced allergy. Migration of human neutrophils and eosinophils towards supernatants of ragweed-stimulated bronchial epithelial cells was analyzed RESULTS: Instillation of ragweed pollen extract, but not of the major allergen or the low molecular weight fraction, induced specific IgG1 , pulmonary infiltration with inflammatory cells, a Th2-associated cytokine signature in pulmonary tissue and impaired lung function. Adenosine aggravated ragweed-induced allergic lung inflammation. In vitro, human neutrophils and eosinophils migrated towards supernatants of bronchial epithelial cells stimulated with ragweed extract only if adenosine was present CONCLUSIONS: Pollen-derived adenosine is a critical factor in ragweed-pollen induced allergic airway inflammation. Future studies aim at therapeutic strategies to control these allergen-independent pathways.