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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.

建议总结