Interleukin-2 and autoimmune disease

IL-2 与自身免疫性疾病

• 批准号: 7994862
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994862
• 关键词: Address; Affect; Animal Experiments; Antibodies; Antigens; Apoptotic; Ascaridil; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Backcrossings; Biochemical; Biochemical Pathway; Biological; Biology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Chronic; Clonal Expansion; Complement; Critiques; Data; Defect; Dendritic Cells; Dendritic cell activation; Development; Disease; Dose; Effector Cell; Event; Experimental Models; Foundations; Gene Expression; Generations; Genes; Genetic; Goals; Graft Rejection; Growth Factor; Hemolytic Anemia; Human Resources; IL2 gene; IL2RA gene; Image; Immune; Immune System Diseases; Immune response; Immunosuppressive Agents; Immunotherapy; In Vitro; Inbred BALB C Mice; Infection; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin-2; Knock-out; Knockout Mice; Lead; Left; Light; Link; Lymphoid; Maintenance; Memory; Mouse Strains; Mus; Natural Immunity; Nature; Paper; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Play; Predisposition; Principal Investigator; Production; Protocols documentation; Publishing; Pump; Reaction; Regulation; Regulatory T-Lymphocyte; Research Personnel; Role; Signal Pathway; Signal Transduction; Staging; Statistical Methods; Stimulus; System; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Thymus Gland; Transduction Gene; Transgenic Mice; Transgenic Model; Transgenic Organisms; Work; allograft rejection; autoreactive T cell; base; cytokine; deprivation; design; fitness; graft vs host disease; imaging modality; in vivo; interest; mouse model; pathogen; prevent; programs; research study; response; sensor; statistics; tumor

DESCRIPTION (provided by applicant): 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 effector/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.7. PROJECT NARRATIVE: Interleukin-2 (IL-2) is a T-cell growth factor that has been used therapeutically to boost immune responses, and IL-2 antagonists have been used as immunosuppressive agents to prevent rejection of allografts and treat graft-vs-host disease. Recent results have shown that IL-2 has a dual biological role it stimulates immune responses by promoting the development of effector and memory cells, and it limits the same responses by virtue of its essential role in the maintenance of functional regulatory T cells (Treg). If we are to use IL-2 or its antagonists as therapeutic agents, and understand its role in immune regulation, we must elucidate how its dual functions are orchestrated. This project uses transgenic and gene knockout mouse models to define why IL-2 is required for Treg survival and function, and how effector and memory responses can be induced in its absence. We will also analyze the mechanisms of the autoimmune disease caused by the absence of IL-2, and determine if different amounts and duration of IL-2 administration can be used to differentially activate effector cells and Treg.

描述（由申请人提供）：白细胞介素-2 （IL-2）是典型的t细胞生长因子，但IL-2的消除会导致严重的免疫失调和全身自身免疫，因为这种细胞因子的必要功能是维持CD4+ CD25+ FoxP3+调节性t淋巴细胞（Treg）。定义IL-2在维持Treg中的作用，以及在缺乏IL-2的情况下效应细胞和记忆细胞是如何产生的，对于理解这种细胞因子的生物学特性和由它的缺乏（更一般地说，由于缺乏Treg）引起的疾病的发病机制，以及开发使用这种细胞因子及其拮抗剂作为治疗性免疫反应调节剂的最佳策略是至关重要的。我们将围绕以下具体目标解决这些问题。1. IL-2在维持功能性Treg中的强制性作用的机制是什么？为了验证IL-2的义务功能是防止Treg的凋亡死亡和促进Treg功能相关基因的表达的假设，我们将定义在缺乏IL-2信号的情况下外周和胸腺中发生的Treg的表型和功能特征。我们将使用删除细胞因子剥夺传感器Bim的遗传方法，在缺乏IL-2的情况下产生可活的Treg。我们将在体外和体内定义这些细胞的功能，并分析这些细胞与在IL-2存在下发育的FoxP3+细胞相比存在缺陷的生化途径。利用逆转录病毒基因转导，我们将研究IL-2与Treg存活和功能之间的生化信号，特别是Akt和Stat5。为了优化IL-2及其拮抗剂的治疗策略，我们将询问不同数量和持续时间的IL-2信号是否会对效应/记忆细胞和Treg产生不同的影响。2. IL-2在效应和记忆反应中的作用是什么？在没有IL-2的情况下，这些反应是如何发展的？为了验证IL-2的功能是为激活的t细胞提供克服Treg控制的能力，并且在缺乏Treg的情况下，反应变得不依赖于IL-2，我们将比较正常受体和正常受体中正常和cd25缺陷t细胞的激活情况，以及我们开发的具有完整淋巴系统的IL-2/CD25xCD28双敲除Treg缺陷小鼠的激活情况。我们还将定义在Treg和IL-2存在和不存在的情况下t细胞活化的生化相关性。我们将检查在缺乏Treg的情况下t细胞识别抗原后的早期事件，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？il -2敲除BALB/c小鼠的自身免疫性疾病以快速发作的溶血性贫血和淋巴细胞增殖为特征，并与IFN-g产生（Th1反应）和树突状细胞（dc）激活显著增强相关。我们将明确t细胞细胞因子反应增强的机制及其对自身免疫性疾病的贡献，并探讨dc因缺乏内源性Treg而自发激活的可能性。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/记忆反应和Treg中的双重作用是如何协调的。这些研究将揭示免疫调节和耐受的机制，并可能有助于优化IL-2及其拮抗剂的治疗方案。项目描述：白细胞介素-2 （IL-2）是一种t细胞生长因子，已被用于增强免疫反应，IL-2拮抗剂已被用作免疫抑制剂，以预防同种异体移植物的排斥反应和治疗移植物抗宿主病。最近的研究结果表明，IL-2具有双重生物学作用，它通过促进效应细胞和记忆细胞的发育来刺激免疫反应，并通过其在维持功能性调节性T细胞（Treg）中的重要作用来限制相同的反应。如果我们要使用IL-2或其拮抗剂作为治疗剂，并了解其在免疫调节中的作用，我们必须阐明其双重功能是如何协调的。该项目使用转基因和基因敲除小鼠模型来定义为什么IL-2是Treg存活和功能所必需的，以及在缺乏IL-2的情况下如何诱导效应和记忆反应。我们还将分析由IL-2缺失引起的自身免疫性疾病的机制，并确定是否可以使用不同剂量和持续时间的IL-2来不同地激活效应细胞和Treg。