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

项目摘要 I型糖尿病(T1D)是一种自身免疫性疾病，在这种疾病中，胰岛素分泌细胞被 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 替换胰岛素以求生存。超过30万美国人患有T1D，另有3万人将被诊断为T1D 仅今年一年。已经确定了T1D的几个遗传易感标记，以及针对T1D的特异性抗体 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。尽管改进了 由于有能力预测对T1D的易感性，目前还没有办法阻止这种疾病的发作。我们打算 通过开发一种新型疫苗来改变这一点，这种疫苗可以用来教导免疫系统不攻击 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，它利用了一类新的非编码RNA， 也就是众所周知的microRNA。通过将特定microRNA的靶序列整合到抗原编码中 基因，我们可以针对特定的细胞类型和细胞状态表达抗原。使用这项技术， 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(Tregs)。初步研究将是 优化microRNA调控系统，将抗原表达靶向抗原提呈细胞 以一种将促进特雷格的诱导的方式。在这些研究之后，我们将评估以下措施的有效性 我们预防非肥胖糖尿病(NOD)小鼠T1D的方法。MicroRNA调控的基因疫苗 将构建编码胰岛抗原，并将用疫苗治疗NOD小鼠，并监测 糖尿病的发展。通过诱导胰岛保护性树突状细胞，我们希望能抑制糖尿病免疫。 应对和预防T1D。这一新的平台，将成为第一个针对特定抗原的疫苗 耐受性细胞，将为预防人类T1D提供强有力的手段。

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.