Identification of Novel Autoantigens in Type 1 Diabetes

1 型糖尿病中新型自身抗原的鉴定

• 批准号: 7193435
• 负责人: MATTEO G LEVISETTI
• 金额: $ 12.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193435
• 关键词: Age; Antibodies; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Beta Cell; Cell Line; Development; Diabetes Mellitus; Disease; Epitopes; Event; Generations; Hyperglycemia; Immune system; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Intervention; Lead; Monoclonal Antibodies; Pathogenesis; Pathologic; Peptides; Phenotype; Play; Preventive; Proteins; Role; Role playing therapy; Spleen; Structure of beta Cell of islet; Surface; Surface Antigens; System; T-Lymphocyte; Therapeutic Intervention; Transfection; autoreactive T cell; islet; lymph nodes; novel; prevent; protein purification

DESCRIPTION (provided by applicant): Type 1 diabetes is an autoimmune disease characterized by the progressive destruction of pancreatic beta-cells that leads to insulinopenia and hyperglycemia. In spite of extensive study, little is known about the initial beta-cell autoantigens that trigger the autoimmune response. This application focuses on identifying the antigens that the immune system targets early in the pathogenesis of diabetes. Specific Aim 1: Characterize autoantibodies to beta cell antigens and identify the antigens. We plan on producing monoclonal antibodies from NOD mice of various ages that are reactive with beta cell surface antigens. These antibodies will be characterized and then used to identify the target antigens present on the surface of the beta cells. These beta cell target antigens will be cloned, sequenced and expressed in cell lines by transfection, and in systems that will allow purification of protein for experimentation. Specific Aim 2: Characterize the T cell reactivity against autoantigens that are identified by the monoclonal antibodies. The generation of peptides, and/or protein, from identified beta-cell autoantigens will allow for the pursuit of autoreactive T cells from the spleen, peripancreatic lymph nodes and islet infiltrates of NOD mice. T cell reactivity against all beta cell autoantigens that are identified will be characterized at the level of protein and T cell peptide epitopes will be characterized. Specific Aim 3: Evaluate the pathogenic role of autoantibodies and T cells. The functional role played by any identified beta-cell antigens in the pathogenesis of diabetes, and the antibodies and T cells which target them, will be examined. The phenotype of T cells reactive with identified antigens will be explored and characterized. Together these aims may lead to an understanding of the early pathologic events in Type 1 diabetes, specifically of the beta-cell antigens that are involved, which is essential for the development of preventive and therapeutic interventions.

描述（由申请人提供）： 1型糖尿病是一种自身免疫性疾病，其特征是胰腺β细胞的进行性破坏，导致胰岛素症和高血糖。尽管进行了广泛的研究，但对触发自身免疫反应的初始β细胞自身抗原知之甚少。该应用的重点是识别免疫系统在糖尿病发病机理早期靶向的抗原。 特定目的1：表征自身抗体的β细胞抗原并识别抗原。我们计划从各种年龄的NOD小鼠中产生与β细胞表面抗原反应性的单克隆抗体。这些抗体将被表征，然后用于鉴定β细胞表面上存在的靶抗原。这些β细胞靶抗原将通过转染克隆，测序和表达，并在可以纯化蛋白质进行实验的系统中。 具体目标2：表征T细胞反应性针对单克隆抗体鉴定的自身抗原。鉴定出的β细胞自身抗原的肽和/或蛋白质的产生将允许从脾脏，周围性淋巴结淋巴结和NOD小鼠的胰岛浸润中追求自动反应性T细胞。对所有鉴定出的β细胞自身抗原的T细胞反应性将在蛋白质水平和T细胞肽表位的水平上进行表征。 特定目标3：评估自身抗体和T细胞的致病作用。将检查任何已鉴定出的β细胞抗原在糖尿病发病机理中所起的功能作用，靶向它们的抗体和T细胞的功能作用将被检查。将探索和表征用已鉴定的抗原反应性的T细胞的表型。 这些目标共同了解1型糖尿病中的早期病理事件，特别是涉及的β细胞抗原，这对于开发预防和治疗性干预措施至关重要。