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

“自身免疫性糖尿病的调节性‘T’细胞控制”。

基本信息

批准号：
8616752
负责人：
Qizhi Tang
金额：
$ 32.48万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616752
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

项目摘要

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）是全球最普遍的慢性儿童疾病之一。除了对患者及其家人的生活质量的负面影响外，该疾病还对社会造成了巨大的经济负担。因此，迫切需要一种治疗溶液，而不是当前的维持治疗。在小鼠模型中，这种治疗方法一种非常成功的治疗方法是自体调节T细胞（TREG）输注。 Treg是CD4+ T淋巴细胞的一小部分，主要负责控制周围病原自身免疫反应。动物模型和患者中的越来越多的证据表明，T1D与致病性T细胞和Treg之间的不平衡有关。 Treg治疗恢复了平衡，并使免疫系统能够恢复自我控制。通过这些令人鼓舞的结果，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。在这个关头，了解TREG功能在控制T1D方面的细胞和分子基础很重要。我们以前的实验表明，从BDC2.5 T细胞受体转基因小鼠（BDC Tregs）分离的胰岛特异性Treg单一输注可以预防和反向NOD小鼠中的糖尿病。 BDC Treg迁移到胰腺淋巴结和胰岛。在胰腺LN中，它们会接合树突状细胞，并通过树突状细胞有效地阻止致病性T细胞的进一步激活。尚未研究BDC Tregs如何阻止2个细胞破坏发炎的胰岛。在此赠款应用中，我们建议通过BDC Tregs系统地研究NOD小鼠中T1D控制的机制。我们将在体内确定BDC Treg的直接细胞靶标，并确定它们对细胞和分子水平胰岛中炎症反应的影响。我们将进一步确定治疗性TREG的分子谱，并确定对其在体内保护作用负责的分子。通过本赠款应用中提出的研究，我们希望更好地了解对T1D进展至关重要的病原事件以及治疗性Treg如何控制这些过程。从这些机械研究中获得的见解将有助于改善基于Treg的细胞疗法的设计，并确定T1D治疗干预的新靶标。