Our laboratory has developed mouse models of allergic eye disease and asthma to enable us to study the pathogenesis of allergic disease in vivo. Our model of allergic conjunctivitis allows us to use topical application of allergens to assess a localized allergic response, and is particularly useful for examining goblet cell hyperproliferation and mast cell degranulation. A number of studies have suggested that allergen exposure in previously sensitized animals causes IgE bearing cells, such as mast cells and basophils, are first activated and work to recruit and activate a number of other effector cells such as T cells and eosinophils. We are particularly interested in characterizing cytokines that may act to downmodulate the earliest phases of the allergic response including IL-10. This project seeks to use a number of different gene disrupted or """"""""knockout"""""""" and transgenic cytokine mice (e.g. IL-10ko, IL-10TG, IL-5ko, IL-5 TG etc.) to examine the events responsible for immediate cytokine production in the mucosal environment upon allergen challenge, including possible production by mast cells, and how cytokines such as IL-10 can help modulate this early response. In particular, we have seen an important role for IL-10 in influencing mast cell stability, something that may prove essential to the prevention both the early stages of allergic responses, including histamine release, and the later phases of allergic disease involving allergic inflammation and influx of eosinophils and other mediators of the allergic phenomenon. We are in the process of defining alterations in the degranulation response in IL-10KO, IL-10 transgenics, and WT control animals to better understand how IL-10 affects the degranulation process at a cellular and molecular level. A secondary factor that we have found to be essential in preventing mast cell activation in our mast cells is GP49 since mice that are genetically deficient in this inhibitory receptor have increased mast cell degranulation after allergen challenge compared with control animals. We are currently examining gp49B KO as well as control gp49A KO animals in order to more fully characterize the role of this inhibitory receptor on mast cells as well as other inflammatory cells involved in the allergic process.
