Novel Strategy to Induce Islet Protective Regulatory T Cells and Prevent Diabetes

诱导胰岛保护性调节 T 细胞和预防糖尿病的新策略

• 批准号: 8000990
• 负责人: Brian D Brown
• 金额: $ 10万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-21 至 2010-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000990
• 关键词: American; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Blood; Cells; Development; Diabetes Mellitus; Diagnosis; Educational process of instructing; Functional RNA; Genes; Genetic Predisposition to Disease; Human; Immune response; Immune system; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; MicroRNAs; Monitor; Natural regeneration; Onset of illness; Patients; Predisposition; Regulatory T-Lymphocyte; System; Technology; Vaccines; autoreactive T cell; cell type; improved; islet; novel; novel strategies; prevent

Project Summary Type I diabetes (T1D) is an autoimmune disorder in which insulin-producing ¿-cells are destroyed by autoreactive T cells. Once the islets are destroyed they do not readily regenerate, and patients must take replacement insulin to survive. More then 300,000 Americans have T1D, and another 30,000 will be diagnosed this year alone. Several genetic susceptibility markers have been identified for T1D, and antibodies specific for islet antigens can be detected in the blood before severe islet destruction takes place. Despite the improved ability to predict susceptibility to T1D, there is currently no way of stopping the onset of the disease. We intend to change this by developing a new type of vaccine that can be used to teach the immune system not to attack insulin-producing cells. Recently, we developed a new antigen targeting platform that exploits a novel class of non-coding RNAs, known as microRNA. By incorporating target sequences for specific microRNAs into an antigen-encoding gene, we could target expression of the antigen to specific cells types and cell states. Using this technology, we will develop a means to induce and expand islet-protective regulatory T cells (Tregs). Initial studies will be carried out to optimize the microRNA-regulated system to target antigen expression to antigen presenting cells in a manner that will promote the induction of Tregs. Following these studies, we will evaluate the effectives of our approach for preventing T1D in non-obese diabetic (NOD) mice. microRNA-regulated gene vaccines encoding islet antigens will be constructed, and NOD mice will be treated with the vaccines, and monitored for the development of diabetes. By inducing islet-protective Tregs, we expect to subdue the diabetogenic immune response and prevent T1D. This novel platform, which will be the first vaccine to target antigen specifically to tolerogenic cells, will provide a powerful means for preventing T1D in humans.

项目概要 I 型糖尿病 (T1D) 是一种自身免疫性疾病，其中胰岛素分泌不足 ¿ - 细胞被破坏 自身反应性 T 细胞一旦被破坏，就不容易再生，患者必须服用 超过 300,000 名美国人患有 T1D，另外 30,000 人将被诊断出来。 仅今年就已鉴定出一些 T1D 遗传易感性标记，以及针对 T1D 的特异性抗体。 尽管改善了，但在严重的胰岛破坏发生之前，可以在血液中检测到胰岛抗原。 预测 T1D 易感性的能力，目前尚无方法阻止该疾病的发作。 通过开发一种新型疫苗来改变这种情况，这种疫苗可以用来教导免疫系统不要攻击 产生胰岛素的细胞。 最近，我们开发了一种新的抗原靶向平台，该平台利用了一类新型非编码 RNA， 通过将特定 microRNA 的靶序列整合到抗原编码中，称为 microRNA。 基因，我们可以利用这项技术将抗原的表达靶向特定的细胞类型和细胞状态， 我们将开发一种方法来诱导和扩增胰岛保护性调节性 T 细胞 (Treg)。 优化 microRNA 调节系统，将抗原表达靶向抗原呈递细胞 在这些研究之后，我们将评估其有效性。 我们在非肥胖糖尿病 (NOD) 小鼠中预防 T1D 的方法。 将构建编码胰岛抗原，并用疫苗治疗 NOD 小鼠，并监测 通过诱导胰岛保护性Tregs，我们期望抑制糖尿病性免疫。 这个新平台将是第一个专门针对抗原的疫苗。 耐受性细胞将为预防人类 T1D 提供强有力的手段。