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Mechanisms and Therapeutic Modulation of T Cell Autoimmune Responses in Sjogren's Syndrome

干燥综合征 T 细胞自身免疫反应的机制和治疗调节

基本信息

批准号：
10214968
负责人：
SEUNGHEE CHA
金额：
$ 53.15万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214968
关键词：
Address Affect Alternative Therapies American Attention Attenuated Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Autologous Biological Assay Biological Response Modifier Therapy Biological Response Modifiers Biology Cellular Immunology Cellular biology Chronic Clinical Development Disease Down-Regulation Exocrine Glands Functional disorder Future Galactose Binding Lectin Galectin 3 Gene Expression Goals Health Helper-Inducer T-Lymphocyte Human Immune Immunology Impairment In Vitro Inbred NOD Mice Individual Inflammation Inflammatory Injections Interferon Type II Interleukin-10 Interleukin-12 Interleukin-17 Interleukin-7 Kinetics Knockout Mice Knowledge Lacrimal gland structure Lead Lentivirus Vector Ligands Mediating Modeling Molecular Molecular Biology Molecular Immunology Mus Oral Oral health Organ Outcome Pathogenicity Pathology Pathway interactions Patients Production Property Regulatory T-Lymphocyte Reporting Research Research Personnel Resistance Salivary Salivary Glands Sjogren&apos s Syndrome System T cell response T-Lymphocyte Testing Therapeutic Xerostomia autoreactivity base chronic autoimmune disease cytokine effective therapy expression vector eye dryness functional disability immunoregulation improved in vivo innovation insight mouse model novel novel therapeutics transcriptome sequencing transcriptomics

项目摘要

Project Summary Sjӧgren’s syndrome (SjS) is an autoimmune disease affecting the oral and systemic health of 4 million Americans. Characterized by chronic inflammation and dysfunction of exocrine glands, SS causes dry mouth, dry eyes and various systemic health problems, with no cure or effective biological therapy available. The objective of this R01 project is to elucidate the negative impact of IL-7 and Th1 cytokines on Treg function in SjS disease, and to test if enhancing TCF1 and Tim-3 in Tregs can improve and enhance their suppressor function, resistance to IL-7/Th1 cytokines, and the ability to ameliorate SjS. Tregs in SjS-prone non-obese diabetic mice are functionally impaired. Pro-inflammatory cytokines, including Th1 cytokines IFNγ and IL-12, can impair the function and stability of Tregs to promote autoimmune inflammation. Our preliminary studies yielded important evidence for the formation of our central hypothesis that IL-7 and Th1 cytokines contribute to aberrant Treg function in SjS conditions, in part by downregulation of TCF1 and Tim-3, and that enhancing the expression/activity of TCF1 and Tim-3 may improve and boost the immunosuppressive function, stability and SjS-attenuating ability of these Tregs. In Aim 1, we will determine if forced expression of TCF1 in Tregs with lentiviral gene expression vectors can improve/enhance their immunosuppressive function, stability under inflammatory conditions, and ability to ameliorate SjS. In vitro Treg functional assays and in vivo Treg transfer to SjS mouse model will be employed. In Aim 2, we will determine if enhancing Tim-3 activity or expression in Tregs can improve and boost their immune-regulatory and SjS-attenuating function. We will enhance Tim-3 activation or expression using several approaches, including in vivo injection of Tim-3 ligand, in vitro stimulation of Tregs with Tim-3 ligand, and force-expressing Tim-3 in Tregs using lentiviral vectors. We will test if enhancing Tim-3 expression/activation can improve/boost the immunosuppressive function of normal and SjS-affected mouse and human Tregs. In Aim 3, we will comprehensively define the transcriptomic changes in mouse and human Tregs associated with SjS and induced by IL-7 and Th1 cytokines with high throughput NGS RNA- sequencing, which will identify new molecular players and pathways underlying the defective Treg function in SjS and induced by IL-7 and Th1 cytokines. Completion of this project will address a critical knowledge gap and advance both basic understanding and translational modulation of Treg function and stability, which could lead to development of Treg-based strategies for ameliorating SjS and various other autoimmune diseases in future.