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：
10133078
负责人：
Scott Matthew Lieberman
金额：
$ 47.62万
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133078
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.

项目概要干燥综合征是一种慢性自身免疫性疾病，其特征是免疫介导的泪腺和唾液腺遭到破坏，导致威胁视力的干眼症，口干，总体生活质量下降。干燥症的免疫发病机制。人们对这种综合征知之甚少，治疗方法也无法阻止自身免疫性破坏迫切需要确定疾病发生的机制来克服。设计有效疗法的障碍。数年（甚至数十年）排除了对人类非肥胖糖尿病（NOD）小鼠的此类研究。产生具有多种特征的泪腺和唾液腺自发性自身免疫重组人类干燥综合征，包括 T 细胞在介导干燥综合征中的核心作用我们最近发现泪腺受到自身免疫攻击。 NOD 小鼠的自身免疫需要白细胞介素 27 (IL27) 和 I 型干扰素 (IFN)。细胞因子非常复杂，具有免疫刺激和免疫调节作用，具体取决于因此，直接靶向 IL27 或 I 型 IFN 可能不适合。我们研究的长期目标是寻找新的治疗方法。我们本提案的目标是确定干燥综合征的治疗目标。 IL27 和 I 型 IFN 驱动 NOD 小鼠泪腺自身免疫的机制我们的中心假设是先天免疫信号（例如，I 型）。 IFN）促进泪腺抗原呈递细胞产生IL27，从而驱动致病我们测试这一假设的具体目标是：(1) 识别泪腺。 IL27 的细胞靶标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型干扰素在驱动中的作用我们将使用基于 NOD 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，以及体外培养来进行这些研究的显着积极影响。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，这将导致新的疗法来阻止鉴于 IL27 和 I 型 IFN 在其他自身免疫性疾病中的作用，这些研究结果也可能导致其他自身免疫性疾病的治疗。