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Tyk2 and Associated Cytokines in Salivary Gland Autoimmunity

Award Number: R01DE032328
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Tyk2 and Associated Cytokines in Salivary Gland Autoimmunity - PROJECT SUMMARY Sjögren’s disease is a chronic autoimmune disease characterized by immune-mediated destruction of salivary and lacrimal glands leading to profound dry mouth and associated oral health complications, vision-threatening dry eye disease, and decreased quality of life. The immunological mechanisms of Sjögren’s are poorly understood, and no disease-modifying therapies have been identified. There is a critical need to define the early immunological mechanisms to identify targets for earlier diagnostics and more effective therapies. Diagnosis occurs years after initiation of the autoimmune process making the study of early mechanisms impractical in humans. Nonobese diabetic (NOD) mice spontaneously develop salivary gland autoimmunity with features similar to Sjögren’s in humans including the characteristic focal lymphocytic sialadenitis that is a hallmark of Sjögren’s in humans. We have recently found that gene-editing to disrupt the Tyk2 gene in NOD mice prevents salivary gland inflammation in a lymphocyte-extrinsic manner. Tyk2 is a non-receptor tyrosine kinase associated with several inflammatory cytokines, and TYK2 gene variants are associated with Sjögren’s in humans. Our goals in this proposal are to define the specific innate immune cell subsets and the upstream cytokines that require Tyk2-mediated signaling for the development of autoimmune salivary gland disease. Our central hypothesis is that interleukin (IL)-12 and IL-23 signaling through Tyk2 in antigen presenting cells within the salivary glands are required to drive the focal lymphocytic sialadenitis. The specific aims to test this hypothesis are: (1) Identify cells that require Tyk2 signaling for salivary gland inflammation in NOD mice; (2) Define the requirements for IL-12 and IL-23 in the development of focal lymphocytic sialadenitis. We will use the NOD mouse-based spontaneous disease model, genetically edited NOD strains, our adoptive transfer model, bone marrow chimeras, in vitro cultures, and in vivo cytokine-blocking therapies to perform these studies. The significant positive impact of completing these studies include defining the mechanisms by which Tyk2 and associated cytokines drive salivary gland autoimmunity, which will lead to development of early diagnostic biomarkers and identification of immune proteins that can be targeted therapeutically in Sjögren’s. Notably, inhibitors of Tyk2 are in development, and IL-12 and IL-23 blocking therapies are already available to treat other autoimmune diseases. Identifying the roles of Tyk2 and associated cytokines in Sjögren’s will help guide future studies of Tyk2 and associated cytokine blocking therapies in subsets of individuals with Sjögren’s.


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 = $519,763 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	3	3/7/2025	NON-COMPETING CONTINUATION	$467,786
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	001	3	5/7/2025	NON-COMPETING CONTINUATION	$51,977
														Subtotal = $519,763

Issue Date FY: 2024 ( Subtotal = $475,939 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	001	2	6/6/2024	NON-COMPETING CONTINUATION	$38,853
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	2	3/21/2024	NON-COMPETING CONTINUATION	$437,086
														Subtotal = $475,939

Issue Date FY: 2023 ( Subtotal = $484,277 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Oral Diseases and Disorders Research	000	1	6/9/2023	NEW	$484,277
														Subtotal = $484,277

Grand Total All Awards = $1,479,979

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Tyk2 and Associated Cytokines in Salivary Gland Autoimmunity

Award Number: R01DE032328

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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