T cells reactive to Hybrid Insulin Peptides (HIPs) as biomarkers in autoimmune diabetes

T 细胞对混合胰岛素肽 (HIP) 产生反应，作为自身免疫性糖尿病的生物标志物

基本信息

批准号：
9455452
负责人：
Rocky Lee Baker
金额：
$ 19.44万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9455452
关键词：
Adoptive Transfer Autoantigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Responses Autoimmunity Beta Cell Biological Assay Biological Markers CD4 Positive T Lymphocytes Cells Chromogranin A Clinical Communities Core Facility Data Detection Development Diabetes Mellitus Diabetic mouse Disease Elements Flow Cytometry Frequencies Future Goals HLA-DQ8 antigen Homologous Gene Human Hybrids Immunology Immunophenotyping Inbred NOD Mice Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Investigation Knowledge Lead Ligands MHC Class II Genes Microbiology Modeling Monitor Organ Outcome Pancreas Pathogenesis Pathogenicity Patients Peptide Library Peptides Phenotype Process Proteins Reagent Research Risk Secretory Vesicles Structure of beta Cell of islet T-Lymphocyte To autoantigen Translating United States National Institutes of Health autoreactive T cell diabetes control diabetogenic enzyme linked immunospot assay human disease human leukocyte antigen testing human model human subject improved insulin dependent diabetes mellitus onset interest islet islet amyloid polypeptide medical schools monocyte mouse model neoantigens neuropeptide Y non-diabetic peripheral blood pre-clinical preclinical study protein aminoacid sequence response tool translational research program

项目摘要

Abstract: T cells reactive to Hybrid Insulin Peptides (HIPs) as biomarkers of autoimmune diabetes An important objective in T1D research is the investigation of autoantigens that activate effector T cells and trigger the inflammatory process in islet beta-cells. We recently identified Hybrid Insulin Peptides (HIPs) as a new class of autoantigens in type 1 diabetes (T1D). These neoantigens are created by the fusion of insulin fragments with peptides from other secretory granule proteins such as chromogranin A (ChgA), islet amyloid polypeptide (IAPP), neuropeptide Y (NPY) or insulin itself. Because insulin is present only in pancreatic beta cells, this discovery might provide an explanation for organ-specific autoimmunity in T1D. Importantly, CD4 T cells responding to HIPs have been isolated from the islets of deceased T1D patients, demonstrating the relevance of these autoantigens to the human disease. We hypothesize that T cells reactive to HIPs can serve as biomarkers of disease. Our goals in this project are (1) to determine the HIP-reactive repertoire of CD4 T cells in NOD mice and (2) to determine the immunophenotype of HIP-reactive T cells in the PBMCs of T1D patients and controls. We will pursue these goals by analyzing T cell reactivity to a panel of HIP peptides in the NOD mouse model of T1D and by testing HLA-DQ8 tetramers loaded with HIP peptides for use in monitoring and selecting HIP-reactive T cells.

摘要：T 细胞对混合胰岛素肽 (HIP) 产生反应，作为自身免疫性糖尿病的生物标志物 T1D 研究的一个重要目标是研究激活效应 T 细胞和触发胰岛β细胞的炎症过程。我们最近确定了混合胰岛素肽 (HIP) 1 型糖尿病 (T1D) 中的新型自身抗原。这些新抗原是由胰岛素融合产生的来自其他分泌颗粒蛋白的肽片段，例如嗜铬粒蛋白 A (ChgA)、胰岛淀粉样蛋白多肽（IAPP）、神经肽Y（NPY）或胰岛素本身。因为胰岛素只存在于胰腺β中细胞，这一发现可能为 T1D 器官特异性自身免疫提供解释。重要的是，CD4T 从已故 T1D 患者的胰岛中分离出对 HIP 做出反应的细胞，这表明这些自身抗原与人类疾病的相关性。我们假设对 HIP 具有反应性的 T 细胞可以发挥作用作为疾病的生物标志物。我们在这个项目中的目标是 (1) 确定 CD4 T 的 HIP 反应谱 NOD 小鼠中的细胞和 (2) 确定 T1D PBMC 中 HIP 反应性 T 细胞的免疫表型患者和对照。我们将通过分析 T 细胞对一组 HIP 肽的反应性来实现这些目标。 NOD T1D 小鼠模型并通过测试负载 HIP 肽的 HLA-DQ8 四聚体用于监测并选择 HIP 反应性 T 细胞。