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Defining the Role of Immunoglobulin G4 (IgG4) in Food-Induced Eosinophilic Esophagitis (EoE)

Award Number: R01AI175232
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/04/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Defining the Role of Immunoglobulin G4 (IgG4) in Food-Induced Eosinophilic Esophagitis (EoE) - PROJECT SUMMARY/ABSTRACT Over the past two decades, eosinophilic esophagitis (EoE) has transformed from a case-reportable disease to a major cause of upper gastrointestinal morbidity. EoE is primarily triggered by food, as diets eliminating common food allergens can lead to long-term disease remission. However, accurate tests to identify food triggers in individual patients do not yet exist because we do not fully understand the mechanisms of this food- induced inflammation. We now know that this inflammation is not mediated by IgE, and diets based on IgE to foods have had limited success. In contrast, another immunoglobulin — IgG4 — is produced locally in the esophagus of EoE patients, and tissue levels of IgG4 correlate with disease activity. Using immunofluorescence (IF), we have generated preliminary data that IgG4 and food proteins co-localize in the esophageal tissue of EoE patients with active disease, which is suggestive of immune complex formation. We have further found that these IgG4-food deposits are located in close proximity to proteins associated with eosinophil activation, antigen presentation, and T cells. Defining a role for IgG4 in the pathogenesis of EoE could fundamentally change our understanding of this condition — and of IgG4 — and could facilitate the development of novel diagnostic tests and therapies for this disease. Our overall hypothesis is that IgG4 contributes to food-induced inflammation in EoE. In Aim 1, we will determine whether IgG4 forms immune complexes with food, which then promote high-avidity interactions to activate eosinophils in the esophageal tissue of patients with food-induced EoE. In Aim 2, we will establish whether dendritic cell activation by IgG4-bound antigen amplifies the underlying T cell immune response in EoE. This will be assessed using 1) a validated milk challenge study where esophageal biopsies will be collected from EoE patients in remission on diet and after milk reintroduction and 2) in vitro stimulation assays using novel milk-specific IgG4 monoclonal antibodies (mAbs) generated from patients with EoE. Our group is uniquely positioned to address this critical knowledge gap because of our access to large EoE populations, our expertise in novel spatial and T cell phenotyping techniques, and our ability to generate IgG4 mAbs for in vitro assays. We expect to find that IgG4 contributes to food-induced inflammation in EoE. Regardless of the outcomes, these results will provide novel insights into the mechanisms of food-induced inflammation in EoE and may fundamentally change our understanding of the pathogenesis of this disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $780,419 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	4	4/6/2026	NON-COMPETING CONTINUATION	$780,419
														Subtotal = $780,419

Issue Date FY: 2025 ( Subtotal = $814,262 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	3	4/11/2025	NON-COMPETING CONTINUATION	$814,262
														Subtotal = $814,262

Issue Date FY: 2024 ( Subtotal = $759,427 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	2	4/10/2024	NON-COMPETING CONTINUATION	$759,427
														Subtotal = $759,427

Issue Date FY: 2023 ( Subtotal = $772,504 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Allergy and Infectious Diseases Research	000	1	4/4/2023	NEW	$772,504
														Subtotal = $772,504

Grand Total All Awards = $3,126,612

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Defining the Role of Immunoglobulin G4 (IgG4) in Food-Induced Eosinophilic Esophagitis (EoE)

Award Number: R01AI175232

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/04/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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