"Regulatory 'T' Cell Control of Autoimmune Diabetes".

描述（由申请人提供）：1型糖尿病（T1D）是全球最流行的慢性儿童疾病之一。除了对患者及其家人的生活质量产生负面影响外，这种疾病还对社会造成重大经济负担。因此，迫切需要一种治愈性解决方案，而不是目前的维持治疗。在小鼠模型中显示非常成功的一种这样的治愈性治疗是输注自体调节性T细胞（TCFs）。T淋巴细胞是CD4+ T淋巴细胞的一小部分，主要负责控制外周中的致病性自身免疫反应。在动物模型和患者中越来越多的证据表明，T1D与致病性T细胞和T细胞之间的失衡有关。Treg疗法恢复平衡，使免疫系统重新获得自我控制。有了这些令人鼓舞的结果，目前正在积极开发基于Treg的治疗的临床试验，并计划于2009年开始。在这个节骨眼上，重要的是要了解Treg在控制T1D中的细胞和分子基础。我们先前的实验证明，单次输注从BDC2.5 T细胞受体转基因小鼠分离的胰岛抗原特异性T细胞（BDC T细胞）可以预防和逆转NOD小鼠的糖尿病。BDC T细胞迁移到胰腺淋巴结和胰岛。在胰腺LN中，它们与树突状细胞结合并有效地阻断树突状细胞对致病性T细胞的进一步激活。BDC如何阻止炎症胰岛中2细胞的破坏还没有研究。在这项授权申请中，我们建议系统地研究T1D控制的NOD小鼠的BDC TTRY的机制。我们将在体内确定BDC TdR的直接细胞靶点，并在细胞和分子水平上确定它们对胰岛中正在进行的炎症反应的影响。我们将进一步确定治疗性TdR的分子谱，并鉴定负责其体内保护作用的分子。通过这项资助申请中提出的研究，我们希望更好地了解T1D进展的关键致病事件以及治疗性TdR如何控制这些过程。从这些机制研究中获得的见解将有助于改进基于Treg的细胞疗法的设计并鉴定用于T1D的治疗性干预的新靶点。 公共卫生相关性：1型糖尿病是一种慢性儿童疾病，由免疫介导的胰岛素产生2细胞的破坏引起。调节性T细胞是一小部分免疫细胞，主要负责预防健康人的不必要的免疫反应。在动物模型中，调节性T细胞治疗可以有效预防和逆转1型糖尿病。本文提出的研究旨在了解调节性T细胞控制疾病的细胞和分子基础。从这些机制研究中获得的见解将有助于改善患者基于调节性T细胞的治疗设计，并确定1型糖尿病治疗干预的新靶点。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is one of the most prevalent chronic childhood diseases worldwide. In addition to its negative impact on quality of life for patients and their families, the disease also poses a significant financial burden on society. Thus, a curative solution, instead of the current maintenance therapy, is urgently needed. One such curative treatment shown to be very successful in mouse models is the infusion of autologous regulatory T cells (Tregs). Tregs are a small subset of CD4+ T lymphocytes that are primarily responsible for controlling pathogenic autoimmune responses in the periphery. Mounting evidence in animal models and patients demonstrates that T1D is associated with an imbalance between pathogenic T cells and Tregs. Treg therapy restores the balance and enables the immune system to regain self-control. With these encouraging results, a clinical trial of Treg-based therapy is being actively developed and is scheduled to start in 2009. At this juncture, it is important to understand the cellular and molecular basis of Treg function in controlling T1D. Our previous experiments demonstrate that a single infusion of islet-antigen-specific Tregs isolated from BDC2.5 T cell receptor transgenic mice (BDC Tregs) can prevent and reverse diabetes in the NOD mice. The BDC Tregs migrate to pancreatic lymph nodes and islets. In the pancreatic LN, they engage dendritic cells and effectively block further activation of pathogenic T cells by dendritic cells. How BDC Tregs halt 2 cell destruction in the inflamed islets has not been studied. In this grant application, we propose to systematically investigate the mechanism of T1D control in the NOD mice by BDC Tregs. We will determine the direct cellular target of BDC Tregs in vivo, and identify their impact on the ongoing inflammatory response in the islets at cellular and molecular levels. We will further determine the molecular profile of the therapeutic Tregs and identify molecule(s) responsible for their protective effect in vivo. Through the studies proposed in this grant application, we expect to gain better understanding of the pathogenic events critical for T1D progression and how therapeutic Tregs control these processes. The insight gained from these mechanistic studies will help to improve the design of Treg- based cellular therapy and to identify new targets for therapeutic intervention of T1D. PUBLIC HEALTH RELEVANCE: Type 1 diabetes is a chronic childhood disease that results from an immune-mediated destruction of the insulin-producing 2 cells. Regulatory T cells constitute a small population of immune cells that is mainly responsible for preventing unwanted immune response in healthy people. In animal models, regulatory T cell therapy can effectively prevent and reverse type 1 diabetes. Studies proposed herein are designed to understand the cellular and molecular basis for regulatory T cell control the disease. The insight gained from these mechanistic studies will help to improve the design of regulatory T cell-based therapy for patients and to identify new targets for therapeutic intervention of type 1 diabetes.