Tyk2 and Associated Cytokines in Salivary Gland Autoimmunity

Tyk2 和唾液腺自身免疫中的相关细胞因子

• 批准号: 10733367
• 负责人: Scott Matthew Lieberman
• 金额: $ 48.43万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733367
• 关键词: Address; Adoptive Transfer; Affect; American; Antigen-Presenting Cells; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; Bone Marrow; Cells; Characteristics; Chimera organism; Complex; Data; Dendritic Cells; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease model; Dry Eye Syndromes; Early Diagnosis; Epithelial Cells; Event; Female; Functional disorder; Future; Genes; Gland; Goals; Histologic; Human; Immune; Immune mediated destruction; Immune signaling; Immune system; Immunologics; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Interleukin-12; Knock-out; Knowledge; Lacrimal gland structure; Lymphocyte; Macrophage; Mediating; Modeling; Monoclonal Antibodies; Mouse Strains; Mus; Natural Killer Cells; Non obese; Oral health; Outcome; Pathogenesis; Phenotype; Protein Tyrosine Kinase; Proteins; Quality of life; Research; Resistance; Role; Saliva; Salivary Gland Diseases; Salivary Glands; Sialadenitis; Signal Transduction; Sjogren' s Syndrome; T-Lymphocyte; TYK2; Testing; Vision; Xerostomia; autoimmune rheumatologic disease; chronic autoimmune disease; conditional knockout; cytokine; diabetic; diagnostic biomarker; disability; effective therapy; genetic variant; immunomodulatory therapies; in vivo; inhibitor; insight; interleukin-23; mouse model; prevent; protective effect; targeted treatment; treatment effect

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.

项目总结