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

项目摘要 I型糖尿病（T1 D）是一种自身免疫性疾病，其中产生胰岛素的细胞被破坏 自身反应性T细胞一旦胰岛被破坏，它们就不容易再生，患者必须服用 替代胰岛素才能生存。超过30万美国人患有T1D，另有3万人将被诊断出 就在今年已经鉴定了T1D的几种遗传易感性标志物，以及T1D特异性抗体。 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。尽管改善了 尽管预测T1D易感性的能力有限，但目前还没有阻止疾病发作的方法。我们打算 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的非编码RNA， 称为microRNA。通过将特定microRNA的靶序列并入抗原编码蛋白中， 基因，我们可以将抗原的表达靶向特定的细胞类型和细胞状态。利用这项技术， 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（Tcells）。初步研究将 进行优化microRNA调节系统，以将抗原表达靶向抗原呈递细胞 以一种能促进诱导甲状腺功能亢进的方式。在这些研究之后，我们将评估 我们在非肥胖糖尿病（NOD）小鼠中预防T1D的方法。microRNA调控的基因疫苗 将构建编码胰岛抗原的疫苗，并用疫苗治疗NOD小鼠，并监测其免疫应答。 糖尿病的发展。通过诱导胰岛保护性T细胞，我们期望抑制糖尿病免疫， 预防T1D。这个新的平台，这将是第一个疫苗，靶向抗原特异性， 致耐受性细胞的研究将为预防人类T1D提供有力的手段。

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.