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

“自身免疫性糖尿病的调节性‘T’细胞控制”。

• 批准号: 8432865
• 负责人: Qizhi Tang
• 金额: $ 31.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432865
• 关键词: Active Sites; Adoptive Transfer; Animal Model; Antibodies; Antigens; Applications Grants; Autoimmune Diabetes; Autoimmune Process; Autoimmune Responses; Autologous; B-Lymphocytes; CD4 Positive T Lymphocytes; Cells; Childhood; Chronic; Clinical Trials; Complex; Dendritic Cells; Dendritic cell activation; Development; Diabetes Mellitus; Diabetes prevention; Disease; Disease Progression; Effector Cell; Environmental Risk Factor; Equilibrium; Eragrostis; Etiology; Event; Family; Funding; Genetic; Grant; Human; IL2RA gene; Image; Immune; Immune response; Immune system; Inbred NOD Mice; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Infusion procedures; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Leukocytes; Lymphoid; Maintenance Therapy; Mediating; Mediator of activation protein; Microscopy; Molecular; Molecular Profiling; Mus; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Organ; Pancreas; Pathogenesis; Patients; Population; Population Dynamics; Process; Quality of life; RNA; Regulatory T-Lymphocyte; Schedule; Self-control as a personality trait; Site; Societies; Solutions; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; autoreactive T cell; base; cellular targeting; design; diabetes control; disorder control; improved; in vivo; insight; insulin dependent diabetes mellitus onset; insulin secretion; islet; knock-down; knockout gene; lymph nodes; macrophage; mouse model; novel; prevent; protective effect; public health relevance; research study; two-photon

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.

描述（由申请人提供）：1 型糖尿病 (T1D) 是全世界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，该疾病还给社会带来了巨大的经济负担。因此，迫切需要一种治疗方案来代替目前的维持治疗。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 (Treg)。 Tregs 是 CD4+ T 淋巴细胞的一小部分，主要负责控制外周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疗法可以恢复平衡并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 的疗法的临床试验正在积极开发中，并计划于 2009 年启动。此时此刻，了解 Treg 功能在控制 T1D 中的细胞和分子基础非常重要。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) 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 Tregs 迁移至胰腺淋巴结和胰岛。在胰腺 LN 中，它们与树突状细胞结合，并有效阻止树突状细胞进一步激活致病性 T 细胞。 BDC Tregs 如何阻止发炎胰岛中的 2 细胞破坏尚未得到研究。在本次资助申请中，我们计划系统地研究 BDC Tregs 在 NOD 小鼠中控制 T1D 的机制。我们将确定体内 BDC Tregs 的直接细胞靶标，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 的分子谱，并确定负责其体内保护作用的分子。通过本次拨款申请中提出的研究，我们希望更好地了解对 T1D 进展至关重要的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 的细胞疗法的设计，并确定 T1D 治疗干预的新靶点。