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

描述（由申请人提供）：1型糖尿病（T1D）是全球最常见的儿童慢性疾病之一。除了对患者及其家属的生活质量产生负面影响外，该疾病还对社会造成重大的经济负担。因此，迫切需要一种治疗性的解决方案，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治疗方法是输注自体调节性T细胞（Tregs）。Tregs是CD4+ T淋巴细胞的一个小亚群，主要负责控制外周的致病性自身免疫反应。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Tregs之间的不平衡有关。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，一项基于treg疗法的临床试验正在积极开展，计划于2009年开始。在这个关键时刻，了解Treg在控制T1D中的细胞和分子基础是很重要的。我们之前的实验表明，单次输注从BDC2.5 T细胞受体转基因小鼠（BDC Tregs）中分离的胰岛抗原特异性Tregs可以预防和逆转NOD小鼠的糖尿病。BDC treg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，有效地阻止树突状细胞进一步激活致病性T细胞。BDC Tregs如何阻止炎症胰岛中2细胞的破坏尚未被研究。在本次拨款申请中，我们建议系统地研究BDC Tregs对NOD小鼠T1D的控制机制。我们将在体内确定BDC Tregs的直接细胞靶点，并在细胞和分子水平上确定它们对胰岛持续炎症反应的影响。我们将进一步确定治疗性Tregs的分子特征，并确定在体内发挥保护作用的分子。通过本次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Tregs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的细胞治疗的设计，并确定T1D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.