Dokument

Summary:
Allergic asthma is a chronic inflammatory disease of the airways based on a dysregulated immune response to innocuous antigens (allergens) with a predominance of Th2-driven activities. According to the hygiene hypothesis, neonatal and early childhood exposure to certain microbes and their products may protect them from the development of allergic responses due to a shift in the balance of T cell subpopulation activities. This concept has been experimentally proven for Gram-negative bacteria in a mouse model representing an eosinophil granulocyte-dominated phenotype using ovalbumin as model allergen. Recently, epidemiological studies revealed a specific association between Staphylococcus sciuri exposure and reduced asthma prevalences. The aim in the first part of this work was to establish a murine model of allergic airway inflammation with a more pronounced contribution of neutrophil granulocytes, using the clinically relevant house dust mite (HDM) allergen. Various asthma-relevant parameters were monitored after exposure to house dust mite extracts from different sources, at a wide range of doses and at various intervals after allergen challenge. It could be revealed that HDM1 from Allergopharma Co. (Hamburg, Germany) elicited the strongest asthma phenotype with a mixed eosinophil and neutrophil airway inflammation, an increased production of serum HDM-IgG1 and subsequent histological changes. This phenotype was also more pronounced in mice sensitized with the highest tested HDM extract concentration (100 µg). It also became evident that neutrophils and eosinophils got involved at different time points of the inflammatory process by the action of different chemotactic factors and their activation thus representing different biological events. In the second part of this work, the Gram-positive bacterium S. sciuri was tested for its potential allergy-protective effect in this model. Exposure to S. sciuri strongly inhibited the generation of HDM extract-induced airway inflammation, as evidenced by a reduction of both eosinophil and neutrophil numbers compared to HDM extract-induced airway inflammation in non-exposed control-animals. This suppression of airway inflammation was accompanied by diminished production of cytokines and chemokines and by an alleviation of goblet cell hyperplasia and mucus production. These data provide the first experimental evidence that exposure to S. sciuri might be protective against the development of allergic airway inflammation and associated pulmonary pathology.

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