Oligoclonal T Cell Expansion and Rheumatoid Arthritis

寡克隆 T 细胞扩增与类风湿关节炎

基本信息

批准号：
8080918
负责人：
Cornelia M. Weyand
金额：
$ 33.45万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-30 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8080918
关键词：
6-Phosphofructo-2-kinase 6-Phosphofructokinase Adult Affect Age Antigen-Presenting Cells Antigens Apoptosis Apoptotic Arterial Fatty Streak Autoantibodies Autoimmune Process Autoimmunity BAX gene BCL1 Oncogene BCL2L11 gene Biological Assay CD28 Antigens CD28 gene CD4 Positive T Lymphocytes CX3CL1 gene Cardiovascular Diseases Cell Aging Cell Count Cell Cycle Cell Cycle Arrest Cell Death Cell Proliferation Cell Survival Cell physiology Cells Cellular Stress Cellular biology Cessation of life Characteristics Chromosomal Stability Chronic Clonal Expansion Competence Contracts Controlled Study Data Death Rate Defect Development Diagnosis Effector Cell Employee Strikes Energy-Generating Resources Enzymes Family Family member Fructose Fructose-2,6-bisphosphatase Functional disorder Generations Genes Glucose Glycolysis Glycolysis Pathway Homeostasis Immune Immune response Immune system Immunocompetence Immunologic Deficiency Syndromes Immunosuppressive Agents Impairment In Situ Nick-End Labeling Individual Induction of Apoptosis Infection Inflammation Inflammatory Influenza vaccination Intention Investigation Joints Kinetics Lesion Life Life Cycle Stages Link Longevity Lymphoid Lymphoma Maintenance Maps Mediating Memory Metabolic Mitochondria Modeling Molecular Molecular Profiling Monitor Natural regeneration Nodal Organ Osteoclasts PMAIP1 gene Pathogenesis Pathway interactions Patients Pattern Peripheral Phenotype Phosphotransferases Predisposition Premature aging syndrome Production Proteins Public Health RNA RNA Interference Recovery Rheumatoid Arthritis Risk Role Sentinel Series Signal Transduction Site Small Interfering RNA Staging Stress Stress Tests Syndrome Synovial Membrane T memory cell T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte TFRC gene Telomerase Telomere Shortening Testing Thymus Gland Tissues Vaccinated Work aged annexin A5 antimicrobial arthropathies base body system bone loss cardiovascular infection cell age cohort cytokine deprivation design enzyme activity exhaust extracellular glucose metabolism human TERT protein immune function immunosenescence improved in vivo influenza virus vaccine killer immunoglobulin-like receptor knock-down macrophage member memory CD4 T lymphocyte metabolomics novel overexpression overpopulation premature pro-apoptotic protein programs receptor repaired research study response senescence telomere tumor

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a quintessential autoimmune syndrome with tissue-destructive chronic inflammatory lesions attacking the synovium and a wide spectrum of extra-articular organs. Mounting evidence emphasizes that RA patients not only generate autoreactive immune responses but have broadly diminished immune competence, manifesting as increased susceptibility to infection, lymphoma, and cardiovascular disease. Over the last decade, this project has been devoted to dissecting the contribution of T cells to RA pathogenesis. Our studies have led to the discovery that patients with RA have premature aging of the immune system. Remodeling of the T cell pool, characterized by shrinkage of T cell diversity and accumulation of end-differentiated memory T cells biased toward pro-inflammatory effector functions, revealed a defect in T cell generation that imposes proliferative stress and causes accelerated T cell aging. The current application will investigate this defect in T cell homeostasis and builds on our preliminary data, demonstrating a striking impairment in the survival of na¿ve CD4 T cells from RA patients when undergoing antigen-driven clonal burst. In search of the underlying molecular defect, we have found that RA patients fail to induce sufficient telomerase during the priming response of na¿ve CD4 T cells. Here, we will investigate the mechanistic links between malfunctioning of the telomere repair apparatus and mitochondrial apoptosis pathways, rendering na¿ve CD4 T cells highly sensitive to apoptosis and undermining T cell replenishment. In Specific Aim 1 we will knock-down telomerase in na¿ve CD4 T cells from RA patients and controls and study the impact on T cell expansion after antigen-driven priming. We will repair the defective induction of hTERT in RA CD4 T cells with the intention of readjusting their apoptosis sensitivity. Specific Aim 2 is centered on molecular mechanisms mediating na¿ve CD4 T cell death with special emphasis on BCL-2 family members that function as survival proteins, pro-apoptotic executioners, or regulators. Guided by preliminary data, we will focus on the death sentinel NOXA which transmits extracellular signals controlling recovery during the CD4 priming response. Experiments have been designed to test whether the survival defect in RA T cells relates to NOXA induction and, in particular, is dependent on the p53 pathway. In Specific Aim 3, we will explore how competition for glucose affects CD4 T cell survival during priming. Specifically, we will examine how insufficient induction of the regulatory enzyme 6-phospofructo-2-kinase/fructose-2,6- biphosphatase in RA CD4 T cells reduces glycolytic flux and renders T cells apoptosis sensitive. Specific Aim 4 will connect the molecular studies on T cell homeostasis with the clinically important question as to what extent defective induction of telomerase and impaired survival of CD4 T cells compromise immunocompetence in RA patients and weaken their anti-microbial immune protection. This specific aim will make use of yearly influenza vaccinations to delineate CD4 T cell expansion and contraction in vivo in a cohort of RA patients. PUBLIC HEALTH REVELANCE. Despite the development of powerful immunosuppressive agents, we have not succeeded yet in curing patients with RA. Indeed, patients treated with effective anti-cytokine biologics are now found to have increased risk for infections and tumors. Evidence has accumulated that the immune system of RA patients has a principal defect and that the chronic inflammation destroying joints and other organs systems may signify diminished and not enhanced immune function. Specifically, patients with RA have premature aging of the immune system, easily diagnosed by the shortening of telomeres in T cells. Here, we will examine how RA patients regenerate T cells in their immune system and why their T cells fail to survive when they are driven by antigen. The studies will include vaccinating RA patients with an influenza vaccine to test whether they can build sufficient T cells to be protected from infection.

描述（由申请人提供）：类风湿性关节炎（RA）是一种典型的自身免疫综合征，其组织破坏性慢性炎症病变攻击滑膜和广泛的关节外器官，越来越多的证据强调，RA 患者不仅会产生自身反应性免疫反应，而且还会产生自身免疫反应。免疫能力普遍下降，表现为对感染、淋巴瘤和心血管疾病的易感性增加。在过去的十年中，该项目一直致力于剖析 T 的贡献。我们的研究发现，RA 患者存在 T 细胞库的过早衰老，其特征是 T 细胞多样性减少和终末分化记忆 T 细胞的积累。 -炎症效应子功能，揭示了 T 细胞生成的缺陷，该缺陷会加速增殖应激并导致 T 细胞衰老。当前的应用将研究 T 细胞稳态的这种缺陷，并以我们的初步数据为基础，证明 na 的存活受到显着损害。 ¿在寻找潜在的分子缺陷时，我们发现 RA 患者在 NA 的启动反应过程中无法诱导足够的端粒酶。在这里，我们将研究端粒修复装置故障与线粒体凋亡途径之间的机制联系，以揭示端粒修复装置故障与线粒体凋亡途径之间的机制联系。 ve CD4 T 细胞对细胞凋亡高度敏感并破坏 T 细胞补充。在特定目标 1 中，我们将敲低端粒酶。我们将修复 RA CD4 T 细胞中 hTERT 的缺陷诱导，旨在重新调整其凋亡敏感性。介导 na 的分子机制ve CD4 T 细胞死亡，特别强调 BCL-2 家族成员，其功能为生存蛋白、促凋亡刽子手或调节剂。在初步数据的指导下，我们将重点关注死亡哨兵 NOXA，它在 CD4 T 细胞死亡过程中传递控制恢复的细胞外信号。实验旨在测试 RA T 细胞的存活缺陷是否与 NOXA 诱导相关，特别是是否依赖于 p53 途径，我们将在特定目标 3 中进行探索。具体而言，我们将研究 RA CD4 T 细胞中调节酶 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶的诱导不足如何导致 T 细胞糖酵解通量。具体目标 4 将 T 细胞稳态的分子研究与临床重要问题联系起来，即端粒酶诱导缺陷程度和细胞存活受损程度。 CD4 T 细胞会损害 RA 患者的免疫能力并削弱其抗微生物免疫保护，这一具体目标将利用每年的流感疫苗接种来描绘一组 RA 患者体内 CD4 T 细胞的扩张和收缩。公众健康启示：尽管开发了强效免疫抑制剂，但我们尚未成功治愈 RA 患者。事实上，目前发现接受有效抗细胞因子生物制剂治疗的患者感染和肿瘤的风险增加。 RA患者的免疫系统有一个主要缺陷，慢性炎症破坏关节和其他器官系统可能意味着免疫功能减弱而不是增强。具体而言，RA患者的免疫系统过早老化，很容易诊断。在这里，我们将研究 RA 患者如何在免疫系统中再生 T 细胞，以及为什么他们的 T 细胞在抗原驱动下无法存活。这些研究将包括为 RA 患者接种流感疫苗。测试他们是否能够构建足够的 T 细胞以免受感染。