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Immunological and Microbial Mechanisms in Food Allergy

Award Number: R01AI126915
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: 11/21/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Immunological and Microbial Mechanisms in Food Allergy - ABSTRACT The high prevalence of food allergy (FA) places many at risk of severe reactions to foods including anaphylaxis (1). Our studies on human subjects with FA and in relevant mouse models have identified changes in regulatory T (Treg) cell populations as playing a pivotal role in disease pathogenesis. Specifically, we have identified a critical role of RORgt+ Treg cells, induced by the gut commensal bacteria, in mediating oral tolerance to food allergens (2, 3). In contrast, FA is associated with defective microbiota-dependent differentiation of RORgt+ Treg cells due to dysbiosis. We identified Resistin like molecule beta (RELMβ), a gut goblet cell cytokine previously linked to the innate immune response to parasitic infections (4-6), as pivotal to FA pathogenesis by promoting dysbiosis and disrupting RORgt+ Treg cell differentiation. Reciprocally, there emerges in FA food allergen-specific Treg cells with a T helper cell type (Th2) cell like phenotype, with high expression of the transcription factor GATA3 and the Th2 cytokines IL-4 (7, 8). These reprogrammed Treg cells play an essential role in amplifying disease pathology, and they decline in patients receiving oral immunotherapy (7, 8). Our recent analysis of circulating Treg cells of human subjects with FA identified Thymic stromal lymphopoietin receptor (TSLPR) as a marker of their Th2 cell-like reprogramming. Accordingly, the focus of this proposal is to identify immune regulatory checkpoints that govern FA and means of resetting them to promote oral tolerance. Our overall hypothesis is that the evolution of FA entails two critical checkpoints each involving a distinct Treg cell population under control of dedicated innate cell and cytokine circuits. The first involves microbiota-dependent Helios– RORgt+ Treg cells generated at the peri-weaning period and thereafter which enforced oral tolerance. This circuit is negatively controlled by RELMb, itself induced by an upstream Tuft cell (IL-25)-ILC2(IL-13) axis (9-11), which predisposes to FA by promoting dysbiosis. The second involves Helios+TSLPR+ Th2 cell-like Treg cells that are positively regulated by IgE/Mast cells and which augment the FA responses. To explore this hypothesis, we will under Aim 1 examine the evolution of the pro-tolerogenic immune response in FA Il4raF709 mice following therapy with anti-RELMb mAb or the acute deletion of the RELMb gene Retnlb. We will also elucidate the mechanisms by which RELMb antagonism resets the gut microbiota to enforce oral tolerance, including the expansion of Lactobacilli species rich in indole metabolites that act via the aryl hydrocarbon receptor (AhR) to suppress FA by inducing RORgt+ Treg cells. Under Aim 2, we will dissect the role of TSLPR on Th2 cell-like reprogrammed Treg cell in disease pathogenesis. These findings will then be extending to studies under Aim 3 on FA subjects to relate changes in serum RELMb and Treg cell populations to dysbiosis and disease severity. The proposed studies will provide fundamental new insights relevant to disease pathogenesis and novel therapeutic approaches to re-establish oral tolerance in FA.


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 = $627,598 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	9	12/30/2025	NON-COMPETING CONTINUATION	$627,598
														Subtotal = $627,598

Issue Date FY: 2025 ( Subtotal = $608,769 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	12/30/2024	NON-COMPETING CONTINUATION	$608,769
														Subtotal = $608,769

Issue Date FY: 2024 ( Subtotal = $627,598 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	7	5/24/2024	NON-COMPETING CONTINUATION	$62,760
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	1/16/2024	NON-COMPETING CONTINUATION	$564,838
2024	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	5	4/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $627,598

Issue Date FY: 2023 ( Subtotal = $627,598 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	2/23/2023	COMPETING CONTINUATION	$627,598
														Subtotal = $627,598

Issue Date FY: 2021 ( Subtotal = $523,250 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	10/21/2020	NON-COMPETING CONTINUATION	$523,250
														Subtotal = $523,250

Issue Date FY: 2020 ( Subtotal = $523,250 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	11/8/2019	NON-COMPETING CONTINUATION	$523,250
														Subtotal = $523,250

Issue Date FY: 2019 ( Subtotal = $542,500 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	10/29/2018	NON-COMPETING CONTINUATION	$542,500
														Subtotal = $542,500

Issue Date FY: 2018 ( Subtotal = $434,500 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	10/27/2017	NON-COMPETING CONTINUATION	$434,500
														Subtotal = $434,500

Issue Date FY: 2017 ( Subtotal = $434,500 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	11/18/2016	NEW	$434,500
														Subtotal = $434,500

Grand Total All Awards = $4,949,563

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Immunological and Microbial Mechanisms in Food Allergy

Award Number: R01AI126915

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: 11/21/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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