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T cells promoting transitions toward autoimmunity

Award Number: U01AI176320
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/18/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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T cells promoting transitions toward autoimmunity - SUMMARY Autoimmune disease results from a combination of immunologic missteps involving multiple genes, cell types and environmental factors. In the proposed studies, we will study how these factors promote the transition from sub-clinical autoimmunity to autoimmune disease by comparing individuals at risk for type 1 diabetes, a disease with a well-defined natural history of sub-clinical autoimmunity, and individuals with Down syndrome (DS), a condition with extremely high risk of developing autoimmune disease. The central hypothesis is that the naïve T cell compartment of at-risk individuals is enriched for potentially pathogenic precursors “poised” to transition to autoreactive effector T cells, and the failure of regulatory mechanisms to restrain this process ultimately results in autoimmune disease. The approach leverages access to cross sectional and longitudinal cohorts at high risk or known to progress to autoimmunity; expertise in the genetics and autoantigen-specific T cells in the context of autoimmunity and expertise in single cell multi-modal analyses. Together, this expertise will allow us to probe T cell states in a manner not yet applied to autoimmunity. In our first two Aims, we will deeply characterize T cells across platforms from at risk subjects and address the role of epigenetics. In Aims 3 and 4 we address the role of external triggers using longitudinal cohorts prospectively tracking trigger events and determine whether autoimmune features are exaggerated in subjects acquiring a second autoimmune disease Aim 1 will determine whether pathogenic precursors are present in the naïve T cell compartment of individuals at risk for autoimmune disease compared to non-risk individuals. Aim 2 will identify cell types that harbor the genetic risk for disease transitions and identify underlying pathways that support pathogenic precursor T cells. Aim 3 will identify external factors that contribute to the transition of pathogenic precursors to effectors, including a prospective longitudinal high-risk cohort with intense at home sample collection to track immune variation bridging trigger events. Aim 4 will determine whether features seen in individuals who transition to T1D are exaggerated in individuals who develop additional autoimmune diseases. Ultimately, the knowledge gained from this work will contribute to staging of disease, selective therapies and establish biomarkers to determine risk of progression and response to therapy.


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: 2025 ( Subtotal = $0 )
2025	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	2	8/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,662,451 )
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	001	2	8/12/2024	SUPPLEMENT FOR EXPANSION	$365,178
2024	2024	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	2	7/25/2024	NON-COMPETING CONTINUATION	$1,297,273
														Subtotal = $1,662,451

Issue Date FY: 2023 ( Subtotal = $1,316,264 )
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Allergy and Infectious Diseases Research	000	1	8/18/2023	NEW	$1,316,264
														Subtotal = $1,316,264

Grand Total All Awards = $2,978,715

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T cells promoting transitions toward autoimmunity

Award Number: U01AI176320

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/18/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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