Grantee Research Project Results

2009 Progress Report: The Role of IgG in Mouse Models of Food Allergy

EPA Grant Number: R834067
Title: The Role of IgG in Mouse Models of Food Allergy
Investigators: Sperling, Anne I. , Bryce, Paul J.
Institution: University of Chicago , Northwestern University
EPA Project Officer: Aja, Hayley
Project Period: June 1, 2009 through May 31, 2011
Project Period Covered by this Report: June 1, 2009 through May 31,2010
Project Amount: $433,100
RFA: Exploratory Investigations in Food Allergy (2007) RFA Text | Recipients Lists
Research Category: Human Health

Objective:

The purpose of this project was to assess the role of IgG and its receptors (the Fcγ receptors) in the responsiveness of food allergy. This would be investigated through collaboration between the two PIs of this research grant, Dr. Anne Sperling at the University of Chicago and Dr. Paul Bryce at Northwestern University. Each PI brings unique skills and knowledge to the project—Dr. Sperling possesses extensive experience in dendritic cells, Th2 immunity and the Fcγ receptors in airway models and Dr. Bryce has developed a murine model of food allergy that displays several hallmark aspects of clinical food allergy. The aims of the research are as follows:

Aim #1: Determine the role of FcγRIII signaling on dendritic cells in the induction of food allergy in a novel murine model.

Aim #2: Determine the role of IgG-mediated processes on anaphylaxis to oral antigen exposure.

Progress Summary:

Our previously published data showed that engagement of CD16 on DCs promoted Th2 sensitization in a mouse model of asthma. Based on this study as well as the studies that suggest FcγRIII (a.k.a CD16) promotes the pathogenesis of anaphylaxis and allergy, we hypothesized that FcγRIII also promotes Th2 sensitization in Dr. Bryce’s SEB-driven mouse model of food allergy. In this model, SEB promotes a dominant TH2 response upon challenge by breaking oral tolerance when orally co-administered with allergen during sensitization. In this model, mice develop food allergy-type symptom scores, as well as increases in blood eosinophils, histamine, anti-allergen IgE and IgG1. However, mice deficient for the FcγRIII receptor had decreases in all of these symptoms of food allergy. Therefore, systemic expression of FcγRIII promotes the systemic Th2 response in the food allergy model, similar to what we previously saw in the mouse model of asthma.

Interestingly, during this period of the project, Dr. Sperling’s group made an unexpected discovery. Because the systemic expression of the activating FcγRIII promotes development of systemic Th2 responses in the food allergy model, we hypothesized that activation of the IgG receptors by allergen-specific IgG immune complexes locally in the gut also would promote food allergy. Surprisingly, the results revealed that local administration of allergen-specific IC abrogates allergic sensitization and induces the subsequent inhibition of Th2 responses upon challenge in a food allergy model. The implication of these data is that this form of allergen administration could lead to desensitization in patients. One of the goals of the next grant period will be to determine the mechanism by which this inhibition occurs.

Finally, to examine the influence of dendritic cells on the induction (sensitization) responses occurring in Dr. Bryce’s model, Dr. Sperling’s examined the role of both FcγRIII and SEB receptors on the dendritic cells in allergic-Th2 type of responses in culture experiments. Interestingly, while FcγRIII on dendritic cells did play a role in the development of Th2 responses, the DC were not being directly affected by the adjuvant (SEB) used in the experimental model. Further, Dr. Bryce’s team has explored the regulation of IgE and IgG activation of mast cells by another important cell in the control of allergic inflammation, the regulatory T cell. These studies determined that these Tregs cells are not altered in frequency or location upon sensitization, but lose their suppressive ability during the course of the food allergy model. Additionally, Dr. Bryce’s team has found that the Tregs directly block anaphylaxis induced from mast cells cross-linking of Fc receptors in vitro. Further studies are underway to determine the role of these regulatory T cells in the maintenance of tolerance to food allergens such as peanuts.

Future Activities:

The major goals of the next reporting period are to:

Determine the Fcγ receptor involved in the decreased allergic response in mice given direct administration of allergen-specific IgG.
Determine the mechanism by which the decrease is mediated in the mice given direct administration of allergen-specific IgG.
Determine whether Tregs are responsible for the loss of gut tolerance to food allergens in our model.

Journal Articles:

No journal articles submitted with this report: View all 6 publications for this project

Progress and Final Reports:

Original Abstract

Final Report

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