Molekulare Pathogenese und Immuntherapie bei allergischem Asthma

Abstract

Asthma in humans is a complex disorder characterized by reversible airway bronchoconstriction, hyperresponsiveness, inflammation and remodeling of the airways. The pattern of allergic inheritance is that of complex polygenic disorder. The mapping of the genome has led to the identification of 20 different loci including a particularly interesting locus situated on the long arm of chromosome 5 (5q31-33). This locus contains the T helper type 2 (T H 2) cytokine gene cluster as well as the gene encoding IL-12p40. In the literature there have been several studies reporting successful treatment of allergic asthma in animal models by repressing the T H 2 type cytokines using local delivery of antibodies against cytokines or their receptors.On the other hand, local administration of T H 1 cytokines such as IL-12 and IFN-y depleted lung eosinophils and reduced AHR. In addition, it has been recently demonstrated that mice deficient for the transcription factor T-bet, either heterozygous or homozygous (T-bet -/-), display, in absence of allergen challenge, a T-cell dependent AHR to methacholine challenge, increased airway inflammation and airway remodeling consistent with human asthma. It thus appear that the mucosal balance between GATA3 and T-bet strongly determines the T cell fate of the mucosal surfaces and that the regulation of this balance is a key factor in understanding T cell-mediated mucosal immune responses.