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The role of peripheral immune cell activity in food-allergy-induced neuroinflammation and demyelination

Award Number: R01AI168563
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Food allergy has been implicated in neuropsychiatric and neurodegenerative disorders. However, the causative role of food allergy in brain dysfunction has been debated, largely due to insufficient pathological evidence and clear underlying mechanisms. Using animal models of food allergy, we and others provided supportive evidence linking food allergy and brain dysfunction by demonstrating that inducing food allergy in otherwise healthy mice resulted in behavior changes associated with neuroinflammation and altered neural activities. We have found that C57BL/6J mice sensitized to a bovine whey allergen, ß-lactoglobulin (BLG, Bos 5 d), do not exhibit overt anaphylactic reactions upon acute allergen challenge but showed anxiety-like and depression-like behavior one day after with elevated plasma levels of allergen-specific IgE and inflammatory cytokines and chemokines. These observations indicated that allergy-induced immune responses are still present in sensitized individuals even in the absence of apparent allergic reactions. Taking advantage of this mouse model of non-anaphylactic cow’s milk allergy (CMA), we subjected BLG-sensitized mice to a repeated allergen exposure regimen by placing them on a whey-containing diet for 2 weeks to simulate frequent allergen consumption by individuals with subclinical reactions. Although no evidence of anaphylaxis or food aversion was detected in the allergen-fed mice, we observed profound cortical demyelination as well as increased blood-brain permeability, perivascular astrocyte hypertrophy, and immune cell presence in their brains associated with significant depression-like behavior. Furthermore, the systemic levels of allergen-specific IgE and other inflammatory mediators remained elevated in these mice. Thus, we hypothesize that CMA-induced cortical demyelination and other neuropathologies result from neuroinflammation orchestrated by sustained activities of brain-infiltrating leukocytes due to repeated allergen exposure. In this project, we will first assess whether sensory, motor, and/or cognitive functions are also affected by the CMA-associated demyelination and neuroinflammatory changes in the brain and whether removing the allergen from the diet reverses the changes in the brain and behavior (Aim 1). We will then investigate the involvement of allergen-stimulated immune cells in the development of neuropathologies by clarifying their role in mediating the peripheral allergic insult to the brain (Aim 2). Finally, we will test whether pharmacological protection of the intestinal barrier prevents aberrant allergen entry during food consumption and reduces CMA-induced neuropathologies (Aim 3). The outcomes of this study will fill our knowledge gaps in the mechanism involved in peripheral-to-central communication and clarify the adverse effects of allergy-mediated chronic inflammation on brain function, prompting early allergy detection to prevent brain dysfunction.


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: 2024 ( Subtotal = $326,732 )
2024	2024	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR STOP 8371	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	3	3/5/2024	NON-COMPETING CONTINUATION	$326,732
														Subtotal = $326,732

Issue Date FY: 2023 ( Subtotal = $722,019 )
2023	2023	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	001	2	7/17/2023	SUPPLEMENT FOR EXPANSION	$351,228
2023	2023	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	2	3/14/2023	NON-COMPETING CONTINUATION	$370,791
														Subtotal = $722,019

Issue Date FY: 2022 ( Subtotal = $382,717 )
2022	2022	UNIVERSITY OF NORTH DAKOTA	264 CENTENNIAL DR	GRAND FORKS	ND	58202	GRAND FORKS	USA	Allergy and Infectious Diseases Research	000	1	4/18/2022	NEW	$382,717
														Subtotal = $382,717

Grand Total All Awards = $1,431,468

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The role of peripheral immune cell activity in food-allergy-induced neuroinflammation and demyelination

Award Number: R01AI168563

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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