TGF-beta1 Induced Islet Antigen-Specific Tolerance in Type 1 Diabetes

描述(由申请人提供)： 这项建议的长期目标是设计一种新的免疫调节疗法，用于诱导自身免疫性(1型)糖尿病的耐受。该提案的具体目的是测试一种基于转化生长因子-β1(转化生长因子-β1)的方法，以诱导能够在人类1型糖尿病小鼠模型中转移自我耐受的胰岛抗原特异性调节性T细胞。这项研究提案的潜在发现将对1型糖尿病患者的治疗具有重要意义。 候选人将使用人类1型糖尿病的非肥胖糖尿病(NOD)小鼠模型进行拟议的研究。实现这些目标的循序渐进的方法将是：(1)从多克隆初始T细胞群体中诱导依赖转化生长因子-β1的胰岛抗原特异性调节T细胞，使用树突状细胞来选择抗原特异性；(2)测试转化生长因子-β1诱导的调节T细胞在逆转NOD小鼠已有糖尿病方面的疗效；以及(3)确定转化生长因子-β1的潜在内源性来源(S)，特别是在新发现在耐受诱导中起重要作用的树突状细胞亚群中。 目前人类1型糖尿病的治疗需要终生胰岛素治疗或长期免疫抑制移植，这两种方法都有很大的风险和不想要的副作用。拟议项目的成功完成将帮助我们设计专门针对自身免疫过程的免疫调节疗法，以治疗这种毁灭性的疾病。 除了具有内在的研究重要性外，拟议的研究还包含作为学习候选人向独立调查人员过渡所需的方法学、理论和概念化的适当工具的必要组成部分。加上西北大学范伯格医学院的有利环境，候选人的赞助人和共同赞助人对候选人的职业发展的奉献和承诺，以及候选人出色的研究背景，这项拟议的研究和培训将提供将这些要素结合在一起的核心力量，并最终有助于实现候选人的职业目标。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to design a novel immunomodulatory therapy for tolerance induction for treatment of autoimmune (type 1) diabetes. The specific aim of the proposal is to test a transforming growth factor-beta 1 (TGF-beta1) based methodology for inducing islet antigen-specific regulatory T cells that are capable of transferring self-tolerance in the mouse model of human type 1 diabetes. The potential findings from this research proposal would have significant implications in treatment of patients with type 1 diabetes. The candidate will perform the proposed studies using the non-obese diabetic (NOD) mouse model of human type 1 diabetes. The step-wise approach for pursuing these goals will be: (1) to induce TGF-beta1 dependent islet antigen-specific regulatory T cells from a polyclonal naive T cell population, using dendritic cells for selecting antigen specificities; (2) to test the therapeutic efficacy of the TGF-beta 1-induced regulatory T cells in reverting established diabetes in the NOD mouse; and (3) to determine the potential endogenous source(s) of TGF-beta1, particularly among dendritic cell subsets which are newly recognized to play an important role in tolerance induction. Current treatment for human type 1 diabetes requires life-long insulin therapy or long-term immunosuppression for transplantation, both of which have significant risks and unwanted side-effects. Successful completion of the proposed project will help us design immunomodulatory therapies that specifically target the autoimmune process for treatment of this devastating disease. In addition to having intrinsic research importance, the proposed research contains the necessary components of serving as a suitable vehicle for learning the methodology, theories, and conceptualizations necessary for transition of the candidate to an independent investigator. Together with the conducive environment at Northwestern University Feinberg School of Medicine, the dedication and commitment of the candidate's sponsor and co-sponsors to the candidate's career development, and the candidate's accomplished research background, this proposed research and training would provide the central force for bringing these elements together and ultimately contribute to fulfillment of the candidate's career goal.