In order for food allergens to initiate an allergic response throughout the body, they must first traffic across the single layer of columnar epithelial cells that line the gastrointestinal tract. We have recently shown that a facilitated antigen sampling mechanism occurs whereby IgE in the intestinal lumen binds to antigens and can be trafficked as a complex across the epithelium by the low-affinity IgE receptor CD23. These antigen-lgE complexes can then act of effector cells such as mast cells, leading to degranulation and alteration of normal physiology of the gut, lung, or skin. In addition, we have shown that subjects with food allergy have detectable CD23 and food-specific IgE levels in the stool, which non-atopic controls do not. We hypothesize that the CD23-mediated uptake mechanism is a critical step in the pathophysiology of food allergy, and appearance of CD23 and IgE in the stool may be a useful non-invasive biomarker of food allergic disease. In these proposed experiments, we will examine the use of stool CD23 as a biomarker in food allergy. We will measure stool CD23 in a group of 110 milk-sensitized individuals and determine if stool CD23 is associated with clinical reactivity to milk. We will follow this group of milk-sensitized individuals longitudinally and determine the association of stool CD23 in the natural history of the disease. And finally, we will determine if oral immunotherapy with or without Xolair (omalizumab) affects the level of stool CD23. In the next series of experiments, we will determine the role of epithelial CD23 in the pathophysiology of experimental food allergy. We have shown that triggering of CD23 leads to an inflammatory response by human intestinal epithelial cells, and we will determine the signaling mechanisms responsible for this activation. In addition, we will construct a triple transgenic mouse expressing human CD23, human FcDRI, and human IgE to test the role of CD23 in antigen sampling, anaphylaxis, and allergen-induced inflammation in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI044236-13
Application #
8234034
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
13
Fiscal Year
2011
Total Cost
$356,471
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Wood, Robert A; Kim, Jennifer S; Lindblad, Robert et al. (2016) A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy. J Allergy Clin Immunol 137:1103-1110.e11
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Roda, G; Jianyu, X; Park, M S et al. (2014) Characterizing CEACAM5 interaction with CD8? and CD1d in intestinal homeostasis. Mucosal Immunol 7:615-24
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Caubet, Jean-Christoph; Masilamani, Madhan; Rivers, Neisha A et al. (2014) Potential non-T cells source of interleukin-4 in food allergy. Pediatr Allergy Immunol 25:243-9
Tordesillas, Leticia; Goswami, Ritobrata; Benedé, Sara et al. (2014) Skin exposure promotes a Th2-dependent sensitization to peanut allergens. J Clin Invest 124:4965-75
Järvinen, Kirsi M; Konstantinou, George N; Pilapil, Mariecel et al. (2013) Intestinal permeability in children with food allergy on specific elimination diets. Pediatr Allergy Immunol 24:589-95
Berin, M C; Wang, W (2013) Reduced severity of peanut-induced anaphylaxis in TLR9-deficient mice is associated with selective defects in humoral immunity. Mucosal Immunol 6:114-21

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