Gut Dendritic Cells and Allergic Sensitization

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Food allergy affects up to 8% of the pediatric population, and approximately 2% of the adult population suffers from food allergy. The mechanisms responsible for allergic sensitization, rather than tolerance, to food proteins is not known. We hypothesize that dendritic cells (DCs) in the gastrointestinal tract are key mediators of sensitization by taking up food proteins and presenting them to T lymphocytes in organized lymphoid tissue of the gastrointestinal tract. We will test this hypothesis using a mouse model of food allergy to the cow's milk allergen beta-lactoglobulin (BLG). C3H/HeJ mice fed BLG plus the adjuvant cholera toxin (CT), but not mice fed BLG alone, develop IgE antibodies against BLG and undergo systemic anaphylaxis when re-challenged with BLG. We will track the uptake of FITC-labelled BLG in the intestinal mucosa after feeding in the context of tolerance (antigen alone) or in the context of allergic sensitization (with CT). We will determine if CT alters the presentation of antigen within the gastrointestinal associated lymphoid tissue. The role of DCs in the development of allergic sensitization to BLG will be assessed by expanding DCs with FltSL, or depleting them with a diptheria toxin-based depletion system prior to sensitization. The effect of DC manipulation on BLG-specific antibody levels, severity of anaphylaxis, and cytokine responses to antigen challenge will be determined. The role of potential inductive sites including Payer's patches (PP) and mesenteric lymph nodes (MLN) will be addressed using two approaches. The first approach will use surgical preparation of intestinal loops with or without a PP, followed by sensitization via the loops to test if PP is necessary for allergic sensitization. Secondly, PP, or PP plus MLN will be ablated by treatment of mice with lymphotoxin-beta-receptor and tumor necrosis factor receptor fusion proteins. The results from these experiments will provide a better understanding of how a normally tolerogenic response to a food protein deviates toward allergic sensitization.