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：
9181377
负责人：
Brian T Fife
金额：
$ 37.13万
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/9181377
关键词：
Alpha Cell Antigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell Biological Markers CD4 Positive T Lymphocytes Cells Clinical Clinical Data Clone Cells Complex Cytotoxic T-Lymphocyte-Associated Protein 4 Data Development Diabetes Mellitus Diabetic mouse Diagnosis Disease Disease remission Early Diagnosis Epitopes Failure Frequencies Glutamate Decarboxylase Goals Human Immune Immune Targeting Immune Tolerance Immune system Immunologic Monitoring 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 experimental study immune function immunological synapse formation innovative technologies insulin dependent diabetes mellitus onset islet mouse model non-diabetic novel novel marker peripheral tolerance prevent public health relevance response tool translational approach translational clinical trial type I diabetic

项目摘要

DESCRIPTION (provided by applicant): 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 orer 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.

描述（由申请人提供）：1型糖尿病（T1D）是由胰腺中胰岛素产生β细胞的自身免疫性T淋巴细胞介导的破坏而产生的。每天多次注射胰岛素是糖尿病患者的救生疗法，它们不能治愈。在Orer中以治愈T1D，我们必须首先识别自反应性T细胞，其次，我们必须将其删除。直到最近，识别细胞一直是一项非常艰巨的任务。但是，肽-MHC四聚体技术的最新进展使我们能够在小鼠模型和患有1型糖尿病的小鼠模型和人类中识别，跟踪和询问单个CD4+ T淋巴细胞克隆。通过拥有在疾病期间研究抗原特异性T细胞的工具和技术，我们将能够评估外周耐受性的分解并检查治疗功效，以选择性地去除或使这些自反应性T细胞作为靶向固化。最近，我们改编了一种灵敏的四聚体富集方案，允许对特定肽的极为罕见的CD4+ T细胞进行鉴定和表型：MHCII复合物。我们假设II类MHC：肽四聚体和富集技术将提供一种灵敏的方法，用于使用临床上的胰岛特异性CD4+ T细胞确定胰岛特异性CD4+ T细胞的数量和激活状态来自T1D患者的可行样品。我们进一步假设使用这种方法对胰岛特异性CD4 T细胞的表征将为T1D诊断和疾病分期提供有用的生物标志物试剂。使用这种技术，我们将确定在糖尿病患者中是否丧失周围耐受性，胰岛β细胞肽表位成为免疫系统的主要靶标。我们预测，具有新发作T1D的个体将具有更多的β细胞肽：与非糖尿病个体相比，具有活化表型的MHCII特异性CD4+ T细胞。有了更好地了解β细胞靶标，我们将能够开发特定的抗原方法，以选择性地消除自毁性T细胞来治愈糖尿病。