Interleukin-2 and autoimmune disease

IL-2 与自身免疫性疾病

• 批准号: 8196707
• 负责人: Abul K. Abbas
• 金额: $ 37.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196707
• 关键词: Acute; Address; Affect; Antigens; Apoptotic; Autoantigens; Autoimmune Diseases; Autoimmune hemolytic anemia; Autoimmunity; Biochemical; Biochemical Pathway; Biological; Biology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Chronic; Clonal Expansion; Data; Defect; Dendritic Cells; Dendritic cell activation; Development; Disease; Dose; Effector Cell; Event; Experimental Models; Failure; Foundations; Gene Expression; Generations; Genes; Genetic; Graft Rejection; Growth Factor; Hemolytic Anemia; IL2RA gene; Image; Immune; Immune System Diseases; Immune response; Immunosuppressive Agents; Immunotherapy; In Vitro; Inbred BALB C Mice; Infection; Interferon Type II; Interleukin-2; Knock-out; Knockout Mice; Light; Link; Lymphoid; Maintenance; Memory; Modeling; Molecular; Mouse Strains; Mus; Natural Immunity; Nature; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Play; Production; Protocols documentation; Regulation; Regulatory T-Lymphocyte; Research Personnel; Role; Signal Pathway; Signal Transduction; Staging; Stimulus; System; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Activation Pathway; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Thymus Gland; Transduction Gene; Transgenic Mice; Transgenic Organisms; allograft rejection; autoreactive T cell; base; cytokine; deprivation; fitness; graft vs host disease; imaging modality; in vivo; interest; mouse model; novel; pathogen; prevent; programs; research study; response; sensor; transcription factor; tumor; two-photon

6. PROJECT SUMMARY/ABSTRACT: Interleukin-2 (IL-2) is the prototypic T-cell growth factor but elimination of IL-2 results in severe immune dysregulation and systemic autoimmunity because the obligatory function of this cytokine is to maintain CD4+ CD25+ FoxP3+ regulatory T-lymphocytes (Treg). Defining the role of IL-2 in the maintenance of Treg, and how effector and memory cells are generated in the absence of IL-2, is fundamental for understanding the biology of this cytokine and the pathogenesis of diseases caused by its absence (and more generally, by the absence of Treg), and also for developing optimal strategies for using this cytokine and its antagonists as therapeutic immune response modifiers. We will address these issues along the following specific aims. 1. What mechanisms underlie the obligatory role of IL-2 in the maintenance of functional Treg? To test the hypothesis that the obligatory functions of IL-2 are to prevent apoptotic death of Treg and to promote expression of genes involved in Treg function, we will define the phenotypic and functional characterisitics of Treg that develop in the periphery and the thymus in the absence of IL-2 signals. We will use the genetic approach of deleting Bim, the sensor of cytokine deprivation, to generate viable Treg in the absence of IL-2. We will define the functions of these cells in vitro and in vivo, and analyze the biochemical pathways that are defective in these cells compared to FoxP3+ cells that develop in the presence of IL-2. Using retroviral gene transduction, we will examine the biochemical signals that link IL-2 to Treg survival and function, particularly Akt and Stat5. We will ask if different amounts and duration of IL-2 signal differentially affect efefctor/memory cells vs Treg, in order to optimize strategies for therapeutic use of IL-2 and its antagonists. 2. What is the role of IL-2 in effector and memory responses, and how do these responses develop in the absence of IL-2? To test the hypothesis that IL-2 functions to provide activated T-cells the capacity to overcome Treg control, and responses become IL-2-independent in the absence of Treg, we will compare the activation of normal and CD25-deficient T-cells in normal recipients and in IL-2/CD25xCD28 double-knockout Treg-deficient mice we have developed that have a full lymphoid system. We will also define the biochemical correlates of T-cell activation in the presence and absence of Treg and IL-2. We will examine the early events after T-cell recognition of antigen in the absence of Treg, using in vivo imaging methods. 3. What is the basis of the immunological disease associated with IL-2 deficiency? The autoimmune disease of IL-2-knockout BALB/c mice is characterized by rapid-onset hemolytic anemia and lymphoproliferation, and is associated with markedly enhanced IFN-g production (Th1 responses) and activation of dendritic cells (DCs). We will define the mechanism of the enhanced T-cell cytokine response and its contribution to the autoimmune disease, and explore the possibility that DCs are "spontaneously" activated b5cause of the absence of endogenous Treg. Thus, this project addresses fundamental issues of the functions of IL-2 and how its dual role in activating effector/memory responses and Treg is orchestrated. These studies will shed light on the mechanisms of immune regulation and tolerance, and may help to optimize protocols for the therapeutic uses of IL-2 and its antagonists.

6.项目总结/摘要： 白细胞介素-2（IL-2）是原型T细胞生长因子，但IL-2的消除导致严重的免疫缺陷。 调节异常和系统性自身免疫，因为这种细胞因子的强制性功能是维持CD 4 + CD 25 + FoxP 3+调节性T淋巴细胞（Treg）。定义IL-2在Treg维持中的作用，以及如何 效应细胞和记忆细胞是在缺乏IL-2的情况下产生的，这是理解生物学的基础。 这种细胞因子的缺乏和由其缺乏引起的疾病的发病机制（更一般地说，由缺乏 的Treg），并且还用于开发使用该细胞因子及其拮抗剂作为治疗剂的最佳策略。 免疫反应调节剂我们将沿着以下具体目标处理这些问题。 1. IL-2在维持功能性Treg中的强制性作用的机制是什么？测试 假设IL-2的强制性功能是防止Treg的凋亡性死亡和促进Treg的凋亡性死亡。 表达的基因参与调节性T细胞功能，我们将定义表型和功能特征， 在没有IL-2信号的情况下在外周和胸腺中发育的Treg。我们将利用基因 删除Bim（细胞因子剥夺的传感器）以在不存在IL-2的情况下产生活Treg的方法。 我们将在体外和体内定义这些细胞的功能，并分析其生物化学途径， 与在IL-2存在下发育的FoxP 3+细胞相比，这些细胞中的FoxP 3+细胞有缺陷。利用逆转录病毒基因 转导，我们将研究将IL-2与Treg存活和功能联系起来的生化信号，特别是 Akt和Stat 5。我们将探讨IL-2信号的不同数量和持续时间是否对效应子/记忆有不同的影响 细胞vs Treg，以优化IL-2及其拮抗剂的治疗用途的策略。 2. IL-2在效应器和记忆反应中的作用是什么？ 缺乏IL-2？为了检验IL-2的功能是为活化的T细胞提供以下能力的假设： 克服Treg控制，并且在Treg不存在的情况下应答变得不依赖于IL-2，我们将比较 正常受体和IL-2/CD 25 xCD 28双敲除受体中正常和CD 25缺陷型T细胞的活化 我们已经开发出具有完整淋巴系统的Treg缺陷小鼠。我们还将定义生物化学 在存在和不存在Treg和IL-2的情况下T细胞活化的相关性。我们将研究早期的事件 在不存在Treg的情况下T细胞识别抗原后，使用体内成像方法。 3.与IL-2缺乏相关的免疫性疾病的基础是什么？自身免疫 IL-2敲除BALB/c小鼠的疾病特征为快速发作的溶血性贫血， 淋巴细胞增殖，并与显著增强的IFN-g产生（Th 1应答）和 树突状细胞（DC）的活化。我们将定义增强的T细胞细胞因子应答的机制， 其对自身免疫性疾病的贡献，并探讨DC“自发”激活的可能性 b5内源性Treg缺乏的原因。 因此，该项目解决了IL-2功能的基本问题，以及它在激活 效应器/记忆应答和Treg是协调的。这些研究将阐明 免疫调节和耐受，并可能有助于优化方案的治疗用途的IL-2及其 对手。