Gastrointestinal TSLP in the Pathogenesis of Food AllergyEPA Grant Number: R834064
Title: Gastrointestinal TSLP in the Pathogenesis of Food Allergy
Investigators: Berin, M. Cecilia
Institution: Mount Sinai School of Medicine
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2008 through November 30, 2010 (Extended to November 30, 2011)
Project Amount: $466,125
RFA: Exploratory Investigations in Food Allergy (2007) RFA Text | Recipients Lists
Research Category: Food Allergy , Health Effects , Health
Food allergy is a major public health problem affecting 6-8% of children in the United States, but there is a dearth of information on pathogenesis or preventative strategies. The proposed studies aim to assess mechanisms of food allergy pathogenesis and identify potential triggers of allergic sensitization. This information would be of value in the design of novel therapeutic approaches and development of public health strategies for the prevention of food allergy. Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that has a central role in the development of allergic inflammation in the skin and lung. In the gastrointestinal tract TSLP has a regulatory function, however we hypothesize that an over-expression of TSLP may promote allergic sensitization to food allergens.
To test the role of TSLP in food allergy, its mechanism of action, and its regulation in the gastrointestinal tract.
We will use murine models of IgE-mediated food allergy to test the role of TSLP in the inductive and effector phases of food allergy. We will use TSLP R-/- mice to test the role of TSLP in oral sensitization to food allergens, allergen-induced anaphylaxis, and allergen-induced gastrointestinal disease. We hypothesize that epithelial cell-derived TSLP conditions gastrointestinal dendritic cells to generate Th2-skewed CD4+ T cells that orchestrate the development of food allergy. We will test the mechanism by which TSLP promotes food allergy by a series of adoptive transfer experiments. Next, we will determine the regulation of TSLP in human intestinal epithelial cells cultured in vitro to define potential physiologic triggers that may contribute to food allergic diseases. Understanding what triggers up-regulate TSLP expression could be important for identifying environmental or dietary triggers that promote food allergy. Our third aim will be to generate a transgenic mouse over-expressing TSLP by intestinal epithelial cells. We hypothesize that this transgenic mouse will be susceptible to the development of food allergy, and in addition to providing evidence for a central role of TSLP in food allergy, it would provide a novel murine model of spontaneous food allergy for testing either the allergenicity of food proteins or the efficacy of novel therapeutics.
The results from the first aim will define mechanisms of experimental food allergy, that is necessary for the design of novel targeted therapeutics. The second aim will identify potentially avoidable triggers of food allergy that could be used in public health approaches for food allergy avoidance. The third aim will provide a novel in vivo model for testing the allergenicity of food proteins.