Mucosal Mechanisms Linking Pulmonary and Gastrointestinal Inflammation/Immunity

Mucosal surfaces are constantly exposed to antigens, infectious agents and the indigenous microbiota. Sequential infections are being increasingly recognized to be a determining factor in the outcome of an immune response to unrelated antigens/infections. In addition, perturbations in the gastrointestinal (GI) microbiota through antibiotic use, dietary changes, acute infection and inflammation can alter immunoregulation in the mucosa. Such events early in life may reduce the predisposition toward atopy later in life and, conversely, a reduction in acute infections and/or alterations of the microbiota in 'more hygienic' lifestyles may promote disease (the 'hygiene hypothesis'). <P> While the influence of prior exposure to an infectious agent on the development of inflammation has been studied in isolated mucosal sites, the extent and mechanisms of the immune interaction between anatomically distant mucosal sites remains to be determined. Evidence is beginning to accumulate for a gut-lung immunoregulatory axis but the mechanisms are unknown. <P> Our hypothesis is that gastrointestinal inflammation (acute or chronic) produces immunoregulatory changes that affect the development and/or manifestation of immune responses in the airways, including changes in regulatory T cell responses and myelopoiesis. <P> In this proposal, we will investigate two potential mechanisms of how the inflammatory response to a gut-restricted pathogen (Citrobacter rodentium, the mouse model of enteropathogenic Escherichia coli, which induces a colon-restricted, Th1-biased immune response) modulates the Th2-mediated immune response to an unrelated allergen (OVA) in the lungs: 1) effects on allergen-specific regulatory and effector T cell polarization in the lungs, lung associated lymph nodes and mesenteric lymph nodes following intranasal allergen challenge and 2) effects on the mobilization and migration of dendritic cell and eosinophil precursors from the bone marrow through the blood and into allergen-challenged lungs. <P> PUBLIC HEALTH RELEVANCE Sequential infections are being increasingly recognized to be a determining factor in the outcome of an immune response to unrelated allergens/infections. In addition, perturbations in the gastrointestinal microbiota through antibiotic use, dietary changes, acute infection and inflammation can alter immunoregulation in the mucosa. Such events early in life may reduce the predisposition toward allergy later in life and, conversely, a reduction in acute infections and/or alterations of the microbiota in 'more hygienic' lifestyles may promote disease (the 'hygiene hypothesis'). The extent and mechanisms of the immune interaction between anatomically distant mucosal sites remains to be determined and the data from this proposal will begin to bridge the gap in our understanding of the mechanisms by which inflammatory changes in GI mucosa can promote or prevent allergic disease in the airways. This information will be critically useful for the future design of therapies to treat or prevent allergic diseases.