Mechanisms of immune tolerance in autoimmune diabetes

自身免疫性糖尿病的免疫耐受机制

基本信息

批准号：
8649238
负责人：
Brian T Fife
金额：
$ 37.14万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8649238
关键词：
Antigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell Biological Markers CD4 Positive T Lymphocytes Cells Clinical Clinical Data Complex Data Development Diabetes Mellitus Diagnosis Disease Disease remission Early Diagnosis Epitopes Failure Frequencies Glutamate Decarboxylase Goals Human Immune Immune Targeting Immune Tolerance Immune system Immunosuppression Inbred NOD Mice Individual Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Lead MHC Class II Genes Measures Mediating Methods Monitor Mus Pancreas Pathogenesis Pathway interactions Patients Peptide/MHC Complex Peptides Peripheral Phenotype Population Protocols documentation Reagent Recurrence Research Role Sampling Self-control as a personality trait Staging System T cell response T-Lymphocyte TNFRSF10A gene Techniques Technology Testing Therapeutic Tissues Treatment Efficacy autoreactive T cell autoreactivity diabetic patient disease diagnosis immune function immunological synapse formation innovative technologies insulin dependent diabetes mellitus onset islet mouse model non-diabetic novel peripheral tolerance prevent public health relevance research study response tool translational approach translational clinical trial type I diabetic

项目摘要

Proposal Summary Type 1 diabetes (T1D) results from the autoimmune T lymphocyte mediated destruction of the insulin producing beta cells in the pancreas. Multiple daily insulin injections are a lifesaving therapy for diabetic patients, they are not a cure. In order to cure T1D we must first identify the self-reactive T cells, and secondly we must remove them. Until recently identifying the cells has been a very difficult task. However, recent advances in peptide-MHC tetramer technology have allowed us to identify, track and interrogate individual CD4+ T lymphocyte clones in both mouse models and humans with type 1 diabetes. By having the tools and technology to study antigen specific T cells during disease, we will be able to assess the breakdown in peripheral tolerance and examine therapeutic efficacy to selectively remove or silence these self-reactive T cells as a targeted cure. We have recently adapted a sensitive tetramer enrichment protocol allowing the identification and phenotyping of exceedingly rare CD4+ T cells of a specific peptide:MHCII complex. We hypothesize that class II MHC:peptide tetramer and enrichment techniques will provide a sensitive and robust method for determining the number and activation status of islet Ag-specific CD4+ T cells using clinically feasible samples from T1D patients. We further hypothesize that characterization of islet Ag-specific CD4 T cells using this approach will provide a useful biomarker reagent for T1D diagnosis and disease staging. Using this technology we will determine if peripheral tolerance is lost in diabetic patients and islet beta cell peptide epitopes become major targets of the immune system. We predict that individuals with new onset T1D will have more beta cell peptide:MHCII specific CD4+ T cells with an activated phenotype than non-diabetic individuals. With a better understanding of beta cell targets, we will be able to develop antigen specific approaches to selectively eliminate self-destructive T cells to cure diabetes.

提案摘要 1 型糖尿病 (T1D) 是由自身免疫 T 淋巴细胞介导的胰岛素破坏引起的在胰腺中产生β细胞。每日多次注射胰岛素是糖尿病患者的救命疗法病人，他们不是治愈方法。为了治愈 T1D，我们首先必须识别自身反应性 T 细胞，其次我们必须消除它们。直到最近，识别细胞一直是一项非常困难的任务。然而，最近肽-MHC 四聚体技术的进步使我们能够识别、跟踪和询问个体患有 1 型糖尿病的小鼠模型和人类中的 CD4+ T 淋巴细胞克隆。通过拥有工具和研究疾病期间抗原特异性 T 细胞的技术，我们将能够评估外周耐受性并检查选择性去除或沉默这些自身反应性 T 的治疗效果细胞作为靶向治疗。我们最近采用了敏感的四聚体富集方案，允许对特定肽：MHCII 复合物的极为罕见的 CD4+ T 细胞进行鉴定和表型分析。我们假设 II 类 MHC：肽四聚体和富集技术将提供灵敏且稳健的临床上测定胰岛Ag特异性CD4+T细胞数量和活化状态的方法来自 T1D 患者的可行样本。我们进一步假设胰岛 Ag 特异性 CD4 T 的表征使用这种方法的细胞将为 T1D 诊断和疾病分期提供有用的生物标志物试剂。使用这项技术我们将确定糖尿病患者和胰岛β细胞肽是否丧失外周耐受性表位成为免疫系统的主要目标。我们预测新发 T1D 患者将与非糖尿病患者相比，具有更多具有激活表型的 β 细胞肽：MHCII 特异性 CD4+ T 细胞个人。通过更好地了解 β 细胞靶标，我们将能够开发抗原特异性选择性消除自毁性 T 细胞来治愈糖尿病的方法。