Influence of the mucosal environment on the regulation of the local immune response in health and allergic disease

Allergic diseases, such as allergic asthma and allergic rhinitis, are increasing in prevalence and affect up to 15% of the Western population. Current medical therapy is aimed at relieving symptoms and mainly focuses on secondary prevention. We here propose a study that better defines the way allergen-specific immune responses are initiated and modulated within the nasal mucosa. Our main focus is how epithelial mediators affect the activity of local immune competent cells. In general, antigen-specific immunity is characterized by the preferential development of specialized subsets of protective T cells, including type 1 and type 2 T helper (Th1 and Th2) cells. At the same time, these effector Th cells are controlled by the simultaneous development of smaller numbers of regulatory (suppressor) T (Tr) cells. All these T cell subsets are derived from the stimulation of uncommitted naïve T cells by antigen-presenting dendritic cells (DCs). The preferential induction of these effector Th cells in response to pathogens depends on the way DCs are primed directly by invading pathogens, as well as indirectly by factors produced by cells in their tissue microenvironment. Allergen-specific responses are causally linked to the presence of allergen-specific type 2 T helper (Th2) cells, whereas non-allergic individuals harbour mainly allergen-specific Th1 or Tr cells. We hypothesize that incorrect regulation or activation of DCs within the local environment contributes to manifestation of allergic disease. Although multiple dendritic sub-types with potential functional specialization have been identified in blood, hardly any data is available on DC sub-types in the airway mucosa. Furthermore there is limited data on epithelial factors that could contribute to local immune regulation or how the epithelium detects pathogenic signals. Important factors in this respect are epithelial cell-derived factors, including type I interferons, epithelial cell-derived thymic stromal lymphopoietin protein (TSLP), tumor growth factor (TGF)-b and IL-10. Each of these factors prime DCs for a characteristic ability to preferentially induce Th1, Th2, or Tr cells respectively. In this project we will firstly phenotypically and functionally characterize different tissue DC sub-types and compare these cells with their blood borne counterparts. Secondly, we will determine the production profile of DC-modulatory factors produced by epithelial cells and test their effect on mucosal DC. Finally, we will specifically focus on the regulation of the expression of epithelial cell-derived TSLP, TGF-b and IL-10 which are known to program DC for the induction of Th2 responses and Tr, respectively. Our close link with the ENT clinic gives us the unique possibility to isolate the relevant cell types from both healthy individuals and allergic rhinitis patients. The definition of the interplay between epithelial cells and DCs will aide in the future development of therapies aimed at curtailing allergic disease.