Tolerance Through Induction of Regulatory T Cells

通过诱导调节性 T 细胞产生耐受

• 批准号: 8117704
• 负责人: DAVID M ROTHSTEIN
• 金额: $ 42.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117704
• 关键词: Allograft Tolerance; Allografting; Antigen-Presenting Cells; Antigens; Autoimmune Process; Autoimmunity; B7/CTLA-4 interaction; Bacterial Antigens; Biochemical Pathway; CD4 Positive T Lymphocytes; Cells; Characteristics; Clinical; Colitis; Collaborations; Data; Development; Disease model; Dose; Effector Cell; Event; Exhibits; Generations; Graft Rejection; Histopathology; Homing; IL2RA gene; Immune response; Immune system; Immunity; Immunobiology; In Vitro; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-10; Lead; Literature; Lymphopenia; Maintenance; Methodology; Modeling; Oral; PTPRC gene; Pathway interactions; Peripheral; Phenotype; Play; Population; Postdoctoral Fellow; Prevention; Principal Investigator; Protein Isoforms; Reagent; Regulation; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; Surface; T-Cell Activation; T-Lymphocyte; Therapeutic; Thymus Gland; Transplantation; Up-Regulation; cytokine; in vitro activity; in vivo; insight; interest; novel; novel therapeutics; peripheral tolerance; prevent; programs; stem; transcription factor

Regulatory CD4 T cells (Treg) play a key role in the prevention of autoimmunity and maintenance of allograft tolerance. For example, in the gut, Treg prevent effector T cells from mounting a destructive inflammatory response to a myriad of non-pathogenic bacterial antigens. Natural Treg arise in the thymus and exhibit a CD45RBLo phenotype characteristic of activated cells. Treg can also be induced, for example, by activation of peripheral T cells in vitro in the presence of Antigen Presenting Cells plus cytokines or in vivo by oral antigen. However, it is generally unclear whether these Treg primarily arise as an outgrowth of preexisted Treg within the CD45RBLo population vs. de novo generation from naive CD45RBHi effector cells. Recent findings suggest that the latter is possible, at least in specialized circumstances. If Treg can be induced de novo, we can delineate the signals involved in differentiation from effector cells to Treg. This would have important clinical implications since this conversion represents a shift in the immune response from immunity to tolerance. Moreover, CTLA-4 upregulation is accompanied by induction of Foxp3, a transcription factor key for Treg development. These changes occur in vitro in isolated T cells and in the absence of T cell activation. Preliminary data reveal that this mAb can prevent IBD caused by CD45RBHI effectors by inducing Treg function, suggesting that alpha-CD45RB initiates de novo conversion of effector cells into Treg in the absence of T cell activation. In Project 2 we aim to determine the mechanism(s) of action of these novel Treg and delineate signals leading to Foxp3 and CTLA-4 induction. This is central to the theme of this PPG, which aims to define peripheral mechanism of tolerance. In Aim 1, we will define the mechanisms by which de novo Treg prevent IBD. In addition to secretion of suppressive cytokines we hypothesize that they inhibit both APCs and T effector cells through CTLA-4/B7 interactions. We will compare the role of CTLA-4/B7 and Foxp3 expression by both induced and natural Treg. Since only a subpopulation of alpha-CD45RB -treated cells expresses CTLA-4, in Aim 2 we will define surface markers that accompany cytoplasmic CTLA-4 expression that can further identify regulatory cells within the population. In Aim 3, we will define the signaling pathways that lead to Treg induction. These studies will provide novel insight into the immunobiology of Treg and the pathways leading to their induction. In turn, this will provide new targets for tolerance induction and the prevention of autoimmunity and transplant rejection. Project 2 integrates with other projects in this PPG on multiple levels.

调节性CD4 T细胞（Treg）在预防自身免疫和维持免疫应答中起关键作用。 同种异体移植耐受例如，在肠道中，Treg阻止效应T细胞进行破坏性的免疫反应。 对无数非致病性细菌抗原的炎症反应。天然Treg在胸腺中产生 并表现出活化细胞的CD45RBLO表型特征。Treg也可以被诱导，例如， 通过在抗原呈递细胞加细胞因子存在下体外激活外周T细胞或体内激活 口服抗原然而，通常不清楚这些Treg是否主要是作为先前存在的免疫缺陷的产物而产生的。 CD45RBLo群体内的Treg与来自初始CD45RBHi效应细胞的从头产生。 最近的研究结果表明，后者是可能的，至少在特殊情况下是可能的。如果Treg可以 通过从头诱导，我们可以描绘参与从效应细胞分化为Treg的信号。这 因为这种转化代表了免疫反应的转变， 从免疫到宽容此外，CTLA-4的上调伴随着Foxp3的诱导，Foxp3是一种 Treg发育的关键转录因子。这些变化发生在体外分离的T细胞和 缺乏T细胞活化。初步研究结果表明，该单克隆抗体对CD45RBHI所致的IBD具有预防作用 通过诱导Treg功能，表明α-CD45 RB启动效应细胞的从头转化 转化为Treg。 在项目2中，我们的目标是确定这些新型Treg的作用机制并描绘信号 导致Foxp3和CTLA-4诱导。这是本PPG主题的核心，旨在定义 外周耐受机制 在目标1中，我们将定义从头Treg预防IBD的机制。除了分泌 我们假设它们通过CTLA-4/B7抑制APC和T效应细胞， 交互.我们将比较CTLA-4/B7和Foxp3表达的作用， 崔格由于只有α-CD45RB处理的细胞亚群表达CTLA-4，在目的2中，我们将定义 伴随细胞质CTLA-4表达的表面标志物，可进一步识别调节细胞 在人口中。在目标3中，我们将定义导致Treg诱导的信号通路。 这些研究将为Treg的免疫生物学和导致其表达的途径提供新的见解。 诱导反过来，这将为诱导耐受和预防自身免疫提供新的靶点 和移植排斥反应项目2在多个层面上与本PPG中的其他项目整合。