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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要干燥病是一种慢性自身免疫性疾病，其特征是免疫介导的唾液腺和泪腺的破坏导致严重的口干和相关的口腔问题健康并发症、威胁视力的干眼病以及生活质量下降。对干燥病的免疫机制知之甚少，并且没有缓解疾病的方法治疗方法已经确定，迫切需要定义早期免疫学。确定早期诊断和更有效治疗目标的机制。发生在自身免疫过程启动数年后，从而研究早期机制在人类中不切实际的非肥胖糖尿病（NOD）小鼠会自发发育唾液腺。自身免疫具有与人类干燥综合征相似的特征，包括特征性病灶我们最近发现，淋巴细胞唾液腺炎是人类干燥综合症的一个标志。基因编辑破坏 NOD 小鼠的 Tyk2 基因可预防唾液腺炎症 Tyk2 是一种与多种淋巴细胞外源性相关的非受体酪氨酸激酶。炎症细胞因子和 TYK2 基因变异与人类干燥综合症有关。该提案的目标是定义特定的先天免疫细胞亚群和上游自身免疫唾液发育需要 Tyk2 介导的信号传导的细胞因子我们的中心假设是白细胞介素 (IL)-12 和 IL-23 信号传导通过唾液腺内抗原呈递细胞中的 Tyk2 需要驱动焦点检验这一假设的具体目的是： (1) 鉴定细胞 NOD 小鼠唾液腺炎症需要 Tyk2 信号传导 (2) 定义要求；我们将使用 NOD 来检测 IL-12 和 IL-23 在局灶性淋巴细胞唾液腺炎中的作用。基于小鼠的自发性疾病模型、基因编辑的 NOD 菌株、我们的过继转移模型、骨髓嵌合体、体外培养物和体内细胞因子阻断疗法完成这些研究的显着积极影响包括定义 Tyk2 和相关细胞因子唾液腺的机制自身免疫，这将导致早期诊断生物标志物的开发和识别可以针对干燥病进行治疗的免疫蛋白，尤其是 Tyk2 抑制剂。正在开发中，IL-12 和 IL-23 阻断疗法已经可用于治疗其他疾病确定 Tyk2 和相关细胞因子在干燥病中的作用。有助于指导 Tyk2 和相关细胞因子阻断疗法在以下子集中的未来研究患有干燥综合症的人。