Mast cell regulation of food allergen induced malaise through GDF15-GFRAL signaling

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Food allergy is associated with a hypersensitive type 2 immune response that develops following sensitization to food proteins. Allergic sensitization elicits the development of adaptive immune memory, characterized by antigen specific Th2 cells and B-cells which produce antibodies of the IgE and IgG1 isotypes. IgE antibodies bind to tissue resident mast cells, and these IgE-mast cell units enable a rapid and exuberant recall response to low quantities of food antigen. Pre-clinical and clinical studies underscore the importance of IgE antibodies in the gastrointestinal manifestation of food allergy, such as abdominal pain, nausea and vomiting, however what mast-cells induce to initiate these symptoms is poorly understood. GDF15 is a stress- induced TGF-b cytokine that mediates anorexia, conditioned taste aversion, and vomiting through its receptor, GFRAL, located on the area postrema. GDF15 can be induced by type 1 and type 2 inflammation, however its role in the context of food allergy is unclear. The objective of this proposal is to study the role of GDF15- GFRAL signaling in driving avoidance behavior to food allergens in allergic mice. Preliminary data in in vivo food allergy models demonstrates GDF15 is rapidly induced upon allergen challenge in a manner largely dependent on IgE, FceR1a expressing cells, and leukotrienes. Using qPCR and FISH of the small intestine and colon from food allergen challenged mice, we find that colonic, but not small intestinal, crypt epithelial cells are enriched in GDF15 transcripts. Interestingly, acute pharmacological blockade of GDF15 ameliorates food allergen aversion in a two-bottle preference test behavioral paradigm. This data suggests that IgE- mediated mast cell activation elicits colonic epithelial GDF15 production, potentially through leukotrienes, to drive allergen aversion. To test this hypothesis two aims will be pursued. Aim 1 will examine the effect of genetic deficiency of GDF15 and GFRAL on food allergen avoidance in vivo using newly generated KO mice on the food allergy susceptible BALB/cJ background strain. GDF15 and GFRAL deficiency’s effect on mast- cell mediated immune responses in experimental food allergy will also be characterized. Aim 2 will examine how IgE mediated mast cell activation initiates GDF15-GFRAL signaling in experimental food allergy using mice genetically or pharmacologically deficient in IgE, mast cells, and leukotrienes. Mast-cell dependent changes in the transcriptome of colonic epithelial cells will too be quantified. Together, these studies will enhance our understanding of how type 2 immune responses in the gastrointestinal tract lead to allergen induced malaise, and may reveal novel targets to prevent complications of oral immunotherapy (OIT). Alongside these studies, the applicant will complete a program of advanced technical and theoretical coursework, clinical electives, and scientific skill building. The research and training detailed in this application will prepare him to pursue a clinically relevant basic science career as a physician scientist.