Autoantigens for Diabetogenic CD4 T Cells

致糖尿病 CD4 T 细胞的自身抗原

• 批准号: 8640158
• 负责人: KATHRYN M HASKINS
• 金额: $ 47.49万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640158
• 关键词: Antigen Presentation; Antigen Targeting; Antigens; Autoantigens; Autoimmune Process; Beta Cell; Biochemical; Biological; Biological Process; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chromogranin A; Data; Diabetes Mellitus; Diagnostic; Disease; Disease Progression; Drug Targeting; Early Diagnosis; Generations; Goals; Health; IA-2 protein; Immunization; In Vitro; Inbred NOD Mice; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Knowledge; Lead; Ligands; Light; Memory; Methods; Modification; Monitor; Mus; Nature; Pathogenesis; Peptides; Post-Translational Protein Processing; Procedures; Process; Proteins; Proteomics; Reagent; Relative (related person); Research; Research Personnel; Role; Secretory Vesicles; Source; Staging; Structure; Surrogate Markers; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tolerogen; Transglutaminases; Work; autoreactive T cell; base; design; in vivo; insight; islet; novel; prevent; public health relevance; research study

DESCRIPTION (provided by applicant): With respect to research on type 1 diabetes (T1D), a major gap in the field has been the lack of reagents for the induction of antigen-specific tolerance. Identification of the beta-cell autoantigens that drive the pathogenic T cells in this disease has been a top priority for researchers since knowledge of these proteins could add considerably to our understanding of how diabetes develops, including the relative importance of antigens arising at different stages of disease. To identify antigens for a long- established panel of highly diabetogenic, NOD-derived T cell clones, we have used biochemical separation procedures and proteomic analysis to isolate proteins from islet beta-cells. This work has led to the recent discovery of a new autoantigen in T1D, the secretory granule protein, chromogranin A. The underlying hypothesis of this project is that the antigenic ligands for this panel of diabetogenic clones are derived from a set of closely related proteins and are generated through a common mechanism. To test this hypothesis, we have designed a project in which our goals are to identify antigens for diabetogenic T cells, define the mechanisms by which they arise, and characterize their biological relevance to disease. Our aims are to: (1) isolate the 2-cell antigens for islet- reactive, diabetogenic CD4 T cell clones, (2) determine the primary structure, including modifications, of antigenic peptides, and (3) determine whether WE14, a peptide from ChgA, can be used as a tolerogen to prevent or delay T1D. Expanding our knowledge of the proteins that are the sources of T cell peptide antigens will allow us to better understand their significance in T1D, and will provide the basis for specific therapeutic intervention at the level of the T cell. These proteins, and the peptide ligands from them, will provide information about autoimmune mechanisms, can be used for induction of antigen-specific tolerance or serve as targets for drug intervention, and may also assist in developing methods for early diagnosis and monitoring disease progression.

描述（由申请人提供）：对于1型糖尿病（T1D）的研究，该领域的主要差距是缺乏用于诱导抗原特异性耐受的试剂。鉴定在这种疾病中驱动致病性 T 细胞的 β 细胞自身抗原一直是研究人员的首要任务，因为对这些蛋白质的了解可以大大增加我们对糖尿病如何发展的理解，包括在疾病的不同阶段产生的抗原的相对重要性。为了鉴定长期建立的高度糖尿病性、NOD 衍生 T 细胞克隆组的抗原，我们使用生化分离程序和蛋白质组分析从胰岛 β 细胞中分离蛋白质。这项工作导致最近在 T1D 中发现了一种新的自身抗原，即分泌颗粒蛋白、嗜铬粒蛋白 A。该项目的基本假设是，这组糖尿病克隆的抗原配体源自一组密切相关的蛋白质，并通过共同机制产生。为了检验这一假设，我们设计了一个项目，其目标是鉴定致糖尿病 T 细胞的抗原，定义它们产生的机制，并表征它们与疾病的生物学相关性。我们的目标是：(1) 分离胰岛反应性、致糖尿病 CD4 T 细胞克隆的 2 细胞抗原，(2) 确定抗原肽的一级结构，包括修饰，以及 (3) 确定 WE14（一种来自 ChgA 的肽）是否可以用作耐受原来预防或延迟 T1D。 扩大我们对作为 T 细胞肽抗原来源的蛋白质的了解，将使我们能够更好地了解它们在 T1D 中的重要性，并将为 T 细胞水平的特异性治疗干预提供基础。这些蛋白质以及它们的肽配体将提供有关自身免疫机制的信息，可用于诱导抗原特异性耐受或作为药物干预的靶标，还可能有助于开发早期诊断和监测疾病进展的方法。