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

描述（由申请人提供）： 该提案的长期目标是设计一种新的免疫调节疗法，用于诱导治疗自身免疫性（1型）糖尿病的耐受性。该提案的具体目的是测试基于转化生长因子-β 1（TGF-β 1）的方法，用于诱导能够在人类1型糖尿病小鼠模型中转移自身耐受性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产生重大影响。 候选人将使用人类1型糖尿病的非肥胖糖尿病（NOD）小鼠模型进行拟定研究。追求这些目标的逐步方法将是：（1）使用树突状细胞选择抗原特异性，从多克隆幼稚T细胞群诱导TGF-β 1依赖性胰岛抗原特异性调节性T细胞;（2）测试TGF-β 1诱导的调节性T细胞在逆转NOD小鼠中已建立的糖尿病中的治疗功效;和（3）确定TGF-β 1的潜在内源性来源，特别是在新近认识到在耐受诱导中起重要作用的树突细胞亚群中。 目前对人类1型糖尿病的治疗需要终身胰岛素治疗或长期免疫抑制移植，这两者都具有显著的风险和不希望的副作用。该项目的成功完成将有助于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过渡到独立调查员所需的方法，理论和概念化的合适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，候选人的赞助商和共同赞助商对候选人职业发展的奉献和承诺，以及候选人完成的研究背景，这项拟议的研究和培训将提供将这些元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.