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

描述(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。除了对患者及其家人的生活质量造成负面影响外，该病还给社会带来了巨大的经济负担。因此，迫切需要一种根治性的解决方案，而不是目前的维持疗法。在小鼠模型中，一种被证明非常成功的治疗方法是输注自体调节性T细胞(Treg)。Tregs是CD4T淋巴细胞的一小部分，主要负责控制外周的病理性自身免疫反应。越来越多的动物模型和患者证据表明，T1D与致病T细胞和Tregs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，基于Treg的治疗的临床试验正在积极开发中，计划于2009年开始。在这一点上，重要的是要了解Treg在控制T1D方面的细胞和分子基础。我们先前的实验证明，从BDC2.5 T细胞受体转基因小鼠分离的胰岛抗原特异性Tregs(BDC Tregs)一次输注可以预防和逆转NOD小鼠的糖尿病。BDC树突状细胞迁移至胰腺淋巴结和胰岛。在胰腺LN，它们与树突状细胞结合，并有效地阻止树突状细胞进一步激活致病T细胞。BDC Tregs如何阻止炎症胰岛中2细胞的破坏还没有研究。在这项资助申请中，我们建议系统地研究BDC Tregs对NOD小鼠T1D的控制机制。我们将确定BDC Tregs在体内的直接细胞靶点，并在细胞和分子水平上确定它们对胰岛正在进行的炎症反应的影响。我们将进一步确定治疗Tregs的分子图谱，并确定其体内保护作用的分子(S)。通过这项拨款申请中提出的研究，我们希望更好地了解T1D进展的关键致病事件，以及治疗性Treg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，并为T1D的治疗干预寻找新的靶点。 公共卫生相关性：1型糖尿病是一种慢性儿童疾病，由免疫介导性破坏产生胰岛素的2细胞所致。调节性T细胞构成了一小部分免疫细胞，主要负责防止健康人不必要的免疫反应。在动物模型中，调节性T细胞治疗可以有效地预防和逆转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进以调节性T细胞为基础的患者治疗的设计，并为1型糖尿病的治疗干预确定新的靶点。

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.