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Th1/Th17 Immune Regulation in Severe Allergic Asthma

Award Number: R03AI153794
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: 02/10/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Th1/Th17 Immune Regulation in Severe Allergic Asthma - Project Summary/Abstract This is the resubmission of a grant entitled “Th1/Th17 Immune Regulation in Severe Allergic Asthma” (1 RO3 AI163794-01) which focuses on the mechanism of dendritic cell (DCs)-mediated regulation of Th1/Th17 immune response in neutrophilic airway inflammation. The overall goal of the resubmission application is to gain new knowledge about how metabolic reprograming of DCs contribute to immune priming and immune-polarizing effector function(s) and how it predisposes and generate the inflammatory milieu in severe asthmatic airways. We know from clinical and experimental evidence that respiratory infections, which are a common trigger for asthma exacerbations and contribute to severe form of the disease, manifested a mixed granulocytic airway inflammation comprising both neutrophils and eosinophils. Moreover, we believe that asthma exacerbations in presence of infections leads to stimulate innate sensor STING (stimulator of interferon genes) pathways, as well as skewing Th1/Th17 immune response in the airways. We recently reported that not only activation and immune-priming function of DCs are coupled to profound alterations of the cellular metabolic state, but also it comprises a DC-specific response modulated by the endogenous key metabolites (Jaiswal et al., Immun. Inflamm. Dis, 2019). New and exciting preliminary data reveal that DC-specific increase of immune responsive gene1 (Irg1), which decarboxylate cis-aconitate to produce immunoregulatory metabolite itaconate, in Th1/Th17 asthmatic lung relative to naïve controls presumably to help resolve airway inflammation. This induction of Irg1 is coupled with itaconate productions in DCs with house dust mite (HDM) and STING stimulations. Results show that exogenous itaconate treatment restored mitochondrial respiration and the capacity of DCs to polarize CD4+ T cells, suggesting an immunoregulatory role of itaconate on DCs immune-priming function(s). The anti- inflammatory effect of itaconate was translated in vivo, where adoptive transfer of itaconate treated DCs reduced airway inflammation and T cell-mediated immune response relative to vehicle-treated DCs. From these pieces of evidence we hypothesize that itaconate plays a distinct regulatory role in lung DCs and can be induced to limit neutrophilic airway inflammation. To test this hypothesis, in Aim1, we will first determine if endogenous itaconate is required for developing airway inflammation and Th1/Th17 immune response using Irg1 knockout mice. In Aim2, we will determine whether exogenous treatment of the itaconate derivative exerts potential anti- inflammatory properties in vivo. Taken together, these studies will expand on the limited knowledge of how Irg1/itaconate axis regulates DC effector function and whether therapeutic interventions targeting the airways could reduce or abolish Th1/Th17 immune response in severe asthma.


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 = -$6,457 )
2024	2022	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Allergy and Infectious Diseases Research	000	2	7/29/2024	NON-COMPETING CONTINUATION	-$6,457
														Subtotal = -$6,457

Issue Date FY: 2022 ( Subtotal = $74,470 )
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Allergy and Infectious Diseases Research	000	2	1/4/2022	NON-COMPETING CONTINUATION	$74,470
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Allergy and Infectious Diseases Research	001	2	8/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $74,470

Issue Date FY: 2021 ( Subtotal = $74,470 )
2021	2021	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Allergy and Infectious Diseases Research	000	1	2/10/2021	NEW	$74,470
														Subtotal = $74,470

Grand Total All Awards = $142,483

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Th1/Th17 Immune Regulation in Severe Allergic Asthma

Award Number: R03AI153794

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: 02/10/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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