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。这 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。诊断 发生在自身免疫过程启动数年后，从而研究早期机制 对人类来说不切实际。非肥胖糖尿病（NOD）小鼠自发发育唾液腺 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 淋巴细胞唾液腺炎是人类干燥病的一个标志。我们最近发现 基因编辑破坏 NOD 小鼠的 Tyk2 基因可预防唾液腺炎症 淋巴细胞外在方式。 Tyk2 是一种非受体酪氨酸激酶，与多种 炎症细胞因子和 TYK2 基因变异与人类干燥症有关。我们的 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 腺体疾病。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 淋巴细胞唾液腺炎。检验这一假设的具体目标是：（1）鉴定细胞 NOD 小鼠唾液腺炎症需要 Tyk2 信号传导； (2)明确要求 IL-12 和 IL-23 在局灶性淋巴细胞唾液腺炎的发展中的作用。我们将使用 NOD 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 进行这些研究。完成这些研究的重大积极影响包括 定义 Tyk2 和相关细胞因子驱动唾液腺的机制 自身免疫，这将导致早期诊断生物标志物的开发和识别 可以针对干燥症进行治疗的免疫蛋白。值得注意的是，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 自身免疫性疾病。确定 Tyk2 和相关细胞因子在干燥遗嘱中的作用 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。