Allergic asthma is an airway disease with high prevalence, which can become associated with chronic inflammatory responses. Besides genetic and environmental factors, the local activation of the mucosal immune system plays a decisive role for the incurrence and perpetuation of the disease. Latest studies have shown that mainly all dendritic cells and T-lymphocytes are relevant.
During the last few years our group showed that pro-inflammatory cytokines and certain transcription factors in T cells are key players for the immunopathogenesis of allergic asthma. In this context we examined two model systems of allergic asthma: the OVA-model as well as the T-bet knockout model. Regarding the OVA-model there could be additionally developed variants of the tolerogenic asthma. Studies of the OVA-model have shown a central role of the transcription factors GATA3 and T-bet in allergic asthma. The functional relevance of T-bet has also been highlighted through the finding that T-bet deficient mice develop a phenotype which is similar to human asthma. This phenotype was found to be mediated by IL-13 and can be adoptively transferred through T-Lymphocytes lacking T-bet. We further found a dysbalance between regulatory T-cells and TH2 effector cells in the lung in this disease. Specifically we have found that protein levels of the IL-6R are increased in the bronchoalveolar lavage of patients with allergic asthma. Moreover, in experimental asthma, we found that local blockade of IL-6R in the lung led to amelioration of allergic asthma because of the induction of regulatory T cells and the repression of Th2 cells.
We also found a therapeutically function of the antiviral cytokines IL-28A, IL-28B, IL-29 (also known as Interferon lambda), when given intranasal in experimental asthma. The positive effect of recombinant IL-28 was accompanied by a reduction of Th2- and Th17 cells. Because of this we analysed IL-28 receptor deficient mice in the OVA-model of allergic asthma. We found out that there have been intensified asthma symptoms in IL-28 deficient mice compared to wild-type littermates. Thereby an increased airway resistance, a higher secretion of IgE and a higher airway inflammation was observed. Additionally, we detected an increased proliferation of Th2- and Th17-cells in the lung of IL-28R deficient mice in the asthma model. Beside this we could monitor a feedback mechanism between IL-28R and IL-28 on the cell membrane of dendritic cells in the lung which regulates the development of Th2- and Th17-cells in allergic asthma. IL-28 receptor deficient dendritic cells secreted increased pro-inflammatory cytokines like IL-6 and less anti-inflammatory cytokines like IFN gamma, IL-12 and IL-10 in the lung.
In further studies we documented the role of IL-2 and the transcription factor NFATc2 in allergic asthma. We showed that NFATc2-deficiency lead to an increased number of CD4+CD25+Foxp3+ regulatory T-cells in the lung resulting in induced immunosuppression in experimental asthma. Our recent focus is on the role of Th17 cells in allergic asthma. Specifically we have found that T-bet deficient mice which exhibit Th17 cell number in the lung have also enhanced levels of IL-6 in the lung. We further found that IL-6 induces the T and B cell transcription factor BATF, which is essential for Th17, Th2 and Tfh cell development in the absence of T-bet.
In the long term we hope that based on these new findings innovating therapy strategies can be developed. Special expectations are focused on the modulation of the proinflammatory Th2-axis as well as the activating of protective T-bet replies.