Cytokines driving T cell dysregulation in lacrimal gland autoimmunity

泪腺自身免疫中驱动 T 细胞失调的细胞因子

基本信息

批准号：
10374829
负责人：
Scott Matthew Lieberman
金额：
$ 48.2万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374829
关键词：
Address Adoptive Transfer Affect American Androgens Animal Model Antigen-Presenting Cells Autoimmune Diseases Autoimmunity Automobile Driving Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene Cells Characteristics Chimera organism Clinical Complex Data Development Diagnosis Disease Disease model Dry Eye Syndromes Etiology Event Gene Expression Genes Genetic Transcription Gland Goals Histologic Homing Human Immune Immune mediated destruction Immune response Immune signaling Immune system Immunologics Immunotherapy In Vitro Inbred NOD Mice Inflammation Interferon Type I Interferons Interleukins Invaded Knowledge Lacrimal gland structure Lead Lymphocyte Mediating Methods Modeling Non obese Oral health Organ Outcome Pathogenicity Pathway interactions Patients Production Quality of life Research Role SCID Mice Salivary Glands Serum Signal Transduction Sjogren&apos s Syndrome Stimulus T-Lymphocyte Testing Tissues Vision Xerostomia autoimmune inflammation autoimmune pathogenesis autoimmune rheumatologic disease base cellular targeting chronic autoimmune disease cytokine design diabetic draining lymph node effective therapy effector T cell human disease immunoregulation in vivo male mouse model new therapeutic target novel novel therapeutics ocular surface prevent programs response

项目摘要

PROJECT SUMMARY Sjögren syndrome is a chronic autoimmune disease characterized by immune-mediated destruction of lacrimal and salivary glands leading to vision-threatening dry eye disease, profound dry mouth, and overall decreased quality of life. The immunopathogenesis of Sjögren syndrome is poorly understood, and treatments fail to halt the autoimmune destruction of the targeted glands. There is a critical need to identify mechanisms of disease initiation to overcome barriers to designing effective therapies. Disease initiation precedes clinical manifestations by years (even decades) precluding such studies in humans. Nonobese diabetic (NOD) mice develop spontaneous autoimmunity of lacrimal and salivary glands with several features resembling Sjögren syndrome in humans including the central role of T cells in mediating the autoimmune attack on these glands. We have recently discovered that lacrimal gland autoimmunity in NOD mice requires interleukin 27 (IL27) and type I interferons (IFN). These cytokines are complex with both immunostimulatory and immunomodulatory effects depending on the context. Thus, directly targeting IL27 or type I IFN may not be appropriate in the treatment of Sjögren syndrome. The long-term goal of our research is to identify new therapeutic targets for Sjögren syndrome. Our objectives in this proposal are to identify mechanisms by which IL27 and type I IFN drive lacrimal gland autoimmunity in the NOD mouse model of Sjögren syndrome. Our central hypothesis is that innate immune signals (eg, type I IFN) promote lacrimal gland antigen presenting cells to produce IL27, which drives pathogenic effector T cells to target lacrimal glands. Our specific aims to test this hypothesis are: (1) Identify the cellular targets of IL27 and downstream effects on effector T cells required for lacrimal gland autoimmunity; (2) Define the upstream triggers of IL27 including the role of type I IFN in driving male-specific lacrimal gland disease. We will use the NOD mouse-based spontaneous disease model, genetically edited NOD strains, our adoptive transfer model, bone marrow chimeras, and in vitro cultures to pursue these studies. The significant positive impact of completing these studies includes identifying mechanisms by which human disease-relevant cytokines drive T cell dysregulation in lacrimal gland autoimmunity, which will lead to novel therapies to halt the autoimmune attack. Given the roles of IL27 and type I IFN in other autoimmune diseases, these findings may lead to therapies for other autoimmune diseases as well.

项目摘要 Sjögren综合征是一种慢性自身免疫性疾病，其特征是免疫介导的破坏泪腺和唾液腺，导致威胁性干眼症，口干深度，总体改善了生活质量。 Sjögren的免疫发病发生综合征了解较少，治疗方法无法阻止自身免疫性破坏靶向腺体。迫切需要确定疾病起步的机制以克服设计有效疗法的障碍。疾病倡议先于临床表现数年（甚至几十年）排除了人类的此类研究。非肥胖糖尿病（点头）小鼠开发具有多个功能的泪和唾液网格的赞助自身免疫性重新组合人类中的Sjögren综合征，包括T细胞在介导的中心作用对这些腺体的自身免疫性攻击。我们最近发现泪腺 NOD小鼠中的自身免疫性需要白介素27（IL27）和I型干扰素（IFN）。这些细胞因子是复杂的，具有免疫刺激和免疫调节作用，取决于在上下文。那是直接针对IL27或I型IFN的目标 Sjögren综合征的治疗。我们研究的长期目标是确定新的 Sjögren综合征的治疗靶标。我们在此提案中的目标是确定 IL27和I型IFN驱动泪腺自身免疫的机制 Sjögren综合征的模型。我们的中心假设是先天免疫信号（例如，I型 ifn）促进富富腺抗原呈现细胞产生IL27，从而驱动致病性效应T细胞靶向泪腺。我们测试该假设的具体目的是：（1）确定 IL27的细胞靶标和下游对泪腺效应T细胞的影响自身免疫性；（2）定义IL27的上游触发器，包括I型IFN在驾驶中的作用男性特异性富集腺疾病。我们将使用基于NOD小鼠的发作性疾病模型，一般编辑的点头菌株，我们采用的转移模型，骨髓嵌合体和体外培养以追求这些研究。完成这些的重大积极影响研究包括识别与人类疾病相关的细胞因子驱动T细胞的机制泪腺自身免疫的失调，这将导致新的疗法停止自动免疫攻击。鉴于IL27和I型IFN在其他自身免疫性疾病中的作用，这些发现也可能导致其他自身免疫性疾病的疗法。