Mechanisms of Endotoxin-induced Breakdown of Tolerance in the Lung

University Of Rochester, Rochester NY

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Abstract

DESCRIPTION (provided by applicant): Asthma is a debilitating inflammatory disease of the respiratory tract that impacts millions of Americans. Animal models have been useful in defining some of the key mechanisms involved in the development of allergen-specific airway inflammation. While much is currently known about initiation of allergic inflammation in naive animals, it is largely unknown how tolerance is established or breaks down in susceptible hosts. This may be particularly important for understanding late-onset asthma in older children and adults where it is likely that tolerance to allergens pre-dates the initiation of allergic inflammation. We therefore propose to study allergic sensitization in tolerized animals, building on novel preliminary data that shows a dose-dependent effect of LPS in breaking tolerance for the induction of pulmonary inflammation. The breakdown of tolerance in mice after administration of high-dose LPS correlates with a failure of regulatory T cells (Tregs) to accumulate in the lung. We plan to use an established model of inhaled tolerance to characterize both the effector T cell (Teff) and Treg responses in lungs after administration of LPS and model allergen. We then will use blocking antibodies and genetically modified mouse strains to examine the importance of lung accumulation of Tregs to the maintenance of tolerance. Furthermore, we will examine how changes in the composition and magnitude of the inflammatory response to differing doses of LPS alters the ability of adaptive Tregs to counteract ongoing inflammation and prevent generation of a Teff response that promotes allergic inflammation. Results from these studies will increase our understanding of the initiation of allergic responses, and may lead to the development of therapies aimed at the avoidance of early stage processes of asthmatic disease. PUBLIC HEALTH RELEVANCE: Asthma is a chronic inflammatory disease of the lung that is initiated through the failure of immunologic tolerance and induction of an inappropriate immune response to otherwise innocuous allergens. Regulatory T cells (Tregs) that migrate to inflamed tissues have been shown to be important in the maintenance of tolerance, but little is known about the importance of lung Tregs in maintaining tolerance to inhaled allergen exposure, or how this process breaks down in asthma. We propose to study the importance of lung Treg accumulation in the maintenance of tolerance, and hope to discover novel mechanisms involved in allergic sensitization that are translational and beneficial to at-risk human populations.