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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.

项目总结 Sjögren综合征是一种以免疫调节为特征的慢性自身免疫性疾病泪腺和唾液腺的破坏导致威胁视力的干眼症，严重口干，总体生活质量下降。Sjögren的免疫发病机制对综合征的了解很少，治疗也未能阻止自体免疫破坏靶向腺。迫切需要确定要克服的疾病启动机制。设计有效疗法的障碍。在临床表现之前，疾病的开始是几年(甚至几十年)就不可能在人类身上进行这样的研究。非肥胖糖尿病(NOD)小鼠发展泪腺和唾液腺的自发性自身免疫具有几个特征类似于人类的Sjögren综合征，包括T细胞在介导对这些腺体的自身免疫攻击。我们最近发现泪腺 NOD小鼠的自身免疫需要白介素27(IL27)和I型干扰素(干扰素)。这些细胞因子是复杂的，具有免疫刺激和免疫调节作用，取决于对上下文的影响。因此，直接靶向IL27或I型干扰素可能不适合于干燥综合征的治疗。我们研究的长期目标是找出新的 Sjögren综合征的治疗目标。我们在这份提案中的目标是确定 IL27和I型干扰素驱动NOD小鼠泪腺自身免疫的机制干燥综合征模型的建立。我们的中心假设是先天免疫信号(例如，I型干扰素)促进泪腺抗原提呈细胞产生IL27，从而推动致病效应器T细胞以泪腺为靶标。我们检验这一假设的具体目标是：(1)确定 IL-27的细胞靶点及其下游对泪腺所需效应T细胞的影响自身免疫；(2)定义IL27的上游触发因素，包括I型干扰素在驾驶中的作用男性特有的泪腺疾病。我们将使用NOD小鼠为基础的自发性疾病模型，基因编辑的NOD菌株，我们的采用转移模型，骨髓嵌合体，以及进行这些研究的体外培养。完成这些任务的重大积极影响研究包括确定人类疾病相关细胞因子驱动T细胞的机制泪腺自身免疫失调，这将导致新的治疗方法来阻止自身免疫性攻击。鉴于IL27和I型干扰素在其他自身免疫性疾病中的作用，这些这一发现也可能导致其他自身免疫性疾病的治疗。