T cells in Lupus

狼疮中的 T 细胞

• 批准号: 10308697
• 负责人: George C Tsokos
• 金额: $ 43.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308697
• 关键词: Address; American; Autoimmunity; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Clinical Research; Consumption; Defect; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Targeting; Gene Expression; Genes; Genetic Transcription; Glycolysis; Human; Immune; Immune Tolerance; Immune response; Immunologist; Immunosuppressive Agents; Infection; Lead; Link; Lupus; Membrane; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Mus; Natural Killer Cells; Nicotinamide adenine dinucleotide; Organ; Organelles; Oxidative Phosphorylation; Pathology; Patients; Performance; Pilot Projects; Predisposition; Prospective Studies; Research; Role; Surface; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Woman; Work; cohort; cytotoxic; cytotoxicity; design; experimental study; improved; infection rate; lupus prone mice; mortality; novel; overexpression; prospective; response; targeted biomarker; targeted delivery; translational scientist

The multitude of mechanisms that lead to general break of tolerance and organ pathology in patients with systemic lupus erythematosus (SLE) have challenged both basic immunologists and translational researchers. Infections remain one of the main causes of morbidity and mortality among patients with SLE despite our significantly improved ability to diagnose and treat infections early and efficiently. Search for genes expressed in T cells from patients with SLE revealed CD38 to be associated with more severe disease and extensive aberrant gene expression. CD8+CD38+ T cells were found expanded in patients with SLE and to be strongly associated with increased infection rates. CD8+CD38+ cells display compromised cytotoxic activity, less amounts of nicotinamide adenine dinucleotide (NAD+), decreased glycolysis and oxidative phosphorylation and decreased expression of molecules responsible for the performance of cytotoxic cell function. In addition, inhibition of CD38 appeared to restore aspects of cytotoxic cell function. The hypothesis which will guide the proposed studies is: increased expression of CD38 on CD8+ cells in patients with SLE and lupus-prone mice compromises their cytotoxic activity and predisposes to infections and drives autoimmunity. Three sets of experiments using human cells and novel mice will be conducted to test the hypothesis. The first will determine how CD38 expression limits cytotoxicity in CD8 cells. The second will explore approaches to enhance cytotoxic responses of SLE CD8+ cells including targeted delivery of drugs to T cells. Whereas, in the third we will conduct a pilot prospective study to determine the value of CD38 expression in identifying patients with SLE prone to infections. The identification of the CD8+CD38+ T cell subset to be expanded in SLE patients and role of CD38 in limiting their cytotoxic activity along with the design of new mice represent novel concepts in the field of lupus. The search for approaches to restore their cytotoxic activity and the clinical study to define them as a biomarker for SLE patients prone to infections represent the translational value of this line of research.

导致耐受性和器官病理学一般破裂的多种机制 全身性红斑狼疮（SLE）的患者对两位基本免疫学家提出了挑战 和翻译研究人员。感染仍然是发病率的主要原因之一， 尽管我们明显提高了诊断能力和 尽早治疗感染。 搜索来自SLE的患者的T细胞中表达的基因显示CD38与 具有更严重的疾病和广泛的异常基因表达。 CD8+ CD38+ T细胞是 发现在SLE患者中扩展，并与感染升高密切相关 费率。 CD8+ CD38+细胞表现出受损的细胞毒性活性，烟酰胺量较少 腺嘌呤二核苷酸（NAD+），糖酵解和氧化磷酸化降低和 负责细胞毒性细胞功能性能的分子表达降低。 另外，抑制CD38似乎还恢复了细胞毒性细胞功能的各个方面。 指导拟议研究的假设是：CD38上的表达增加 SLE和容易发生小鼠患者的CD8+细胞损害其细胞毒性活性和 易于感染和驱动自身免疫性。使用人类细胞的三组实验 并将进行新的小鼠以检验假设。第一个将决定CD38的方式 表达限制了CD8细胞中的细胞毒性。第二个将探索增强的方法 SLE CD8+细胞的细胞毒性反应，包括将药物靶向递送到T细胞。然而， 在第三个中，我们将进行一项试验前瞻性研究，以确定CD38表达的价值 在识别容易感染的SLE患者时。 鉴定CD8+ CD38+ T细胞子集将在SLE患者中扩展和 CD38限制其细胞毒性活性以及新鼠标的设计代表了新颖 狼疮领域的概念。寻找方法以恢复其细胞毒性活性和 将其定义为容易感染的SLE患者的生物标志物的临床研究代表 这一研究线的翻译价值。