Mast cells (MCs) have been implicated in a variety of diseases affecting the gastrointestinal (GI) tract, but their precise role in GI inflammatory reactions has not been defined. Recently, MCs have been identified as a source of a variety of multifunctional cytokines which may influence many aspects of GI inflammation. In the initial funding period of this proposal, we have developed and defined a model system to examine the role of MCs in GI inflammatory processes in vivo using normal (+/+) mice, MC-deficient W/W mice, and W/W mice which have had their MC populations reconstituted in local GI sites by the injection of bone marrow cultured MCs derived from the congenic normal (+/+) littermates. These mice provide a novel way to examine GI reactions in the presence or absence of MCs and can be used to define precisely the influences of MCs during biologic or inflammatory responses. We propose to use this model system to test the hypothesis that MC cytokine production is an important pathophysiologic mechanism involved in certain models of anaphylaxis involving the GI tract. We will examine the role of MC cytokine production during local IgE-, and MC-dependent gastric inflammation, passive (IgE-dependent) systemic anaphylaxis, and active systemic anaphylaxis. Using quantitative methods, we will determine the influence of MCs on the changes in vascular permeability and leukocyte infiltration associated with passive (IgE-dependent) and active systemic anaphylaxis. We will also define the participation of TNF-a, IL-a, and IL-6 from MCs and/or other cells, in each of these reactions. We will analyze GI tissues for the expression of mRNA and product for these cytokines. The role of the MC in the production of the cytokines identified in each reaction will be determined by comparing the levels of cytokine mRNA and products expressed in normal (+/+) mice, MC-deficient W/W mice, and MC- reconstituted W/W mice. The MCs or other cell types expressing mRNA for these cytokines will be identified by in situ hybridization. Finally, we will examine the potential interactions between MCs and the intestinal epithelium using combined in vitro and in vivo approach to define the role of MC mediator/cytokine production to the processes of defensin secretion by Paneth cells or IgA secretion across the intestinal epithelium.
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