Assessment of Allergic Responses to Food Proteins Using a Novel and Sensitive Adjuvant-Free Ingestion-Based Mouse ModelEPA Grant Number: R834825
Title: Assessment of Allergic Responses to Food Proteins Using a Novel and Sensitive Adjuvant-Free Ingestion-Based Mouse Model
Investigators: Oettgen, Hans C
Institution: Children’s Hospital, Boston
EPA Project Officer: McOliver, Cynthia
Project Period: September 15, 2010 through September 14, 2012 (Extended to September 14, 2013)
Project Amount: $424,803
RFA: Approaches to Assessing Potential Food Allergy from Genetically Engineered Plants (2009) RFA Text | Recipients Lists
Research Category: Food Allergy , Health
The goal of this project is to test the utility of a strain of mice, genetically engineered to be exquisitely sensitive to allergens, as a probe for allergenicity of food proteins.
Although models of food protein allergenicity, based on linear and nonlinear protein structure (epitopes), have been developed, these are imperfect. Robust in vivo assays of responses to ingested antigens are needed both to validate structural predictions and to test effects of the food matrix within which protein(s) are presented. Development of in vivo models of food allergy has proven difficult because animals, like humans, are naturally tolerant to ingested proteins. In the mouse food allergy models that have been described, immune sensitization requires unphysiological manipulations, including the feeding of strong gut adjuvants (cholera toxin) or allergen immunization via sites more susceptible than the gastrointestinal tract (intraperitoneal injection or epicutaneous application as in EPA R833133).
We have used mice with heightened IL-4 receptor (IL-4R) sensitivity as probes for allergic responses. We have established that F709 mice, engineered to activate the IL-4Rα-chain (IL-4Rα) are readily sensitized to ingested allergens without exogenous adjuvants or parenteral priming. Based on their hair-trigger sensitivity to IL-4, these animals develop intense IgE responses and severe anaphylactic reactions upon food challenge. This is a novel and unique phenotype in murine allergy models.
Hypothesis: F709 mice, which are inherently allergen-sensitive, will provide a predictive probe of food protein allergenicity applicable to complex mixtures such as genetically modified foods.
Mice will be enterally sensitized and then challenged with a panel of foods known to be allergens in humans as well as foods not associated with allergy. Anaphylaxis, food protein specific immune responses (IgE, IgG1) and mast cell activation will be assessed. Intestinal and systemic cytokine responses as well as T cell phenotypes will be determined and the correlation of each of these indicators with the allergenicity of the inciting food evaluated.
It is anticipated that this study will validate the utility of F709 mice as sensors for food protein allergenicity. Such an in vivo model would be invaluable in testing food protein allergenicity in a real physiologic setting where foods are ingested in a complex matrix of proteins, lipids and glycans and sometimes following genetic modification.