Hybrid Peptides as Autoantigens for Diabetogenic CD4 T Cells

杂合肽作为致糖尿病 CD4 T 细胞的自身抗原

• 批准号: 9126167
• 负责人: KATHRYN M HASKINS
• 金额: $ 56.77万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126167
• 关键词: Antigen Targeting; Antigens; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Beta Cell; Biological Markers; C-Peptide; CD4 Positive T Lymphocytes; Cell Extracts; Chromogranin A; Collaborations; Data; Development; Diagnosis; Disease; Generations; Goals; HLA-DQ8 antigen; Human; Hybrids; In Vitro; Inbred NOD Mice; Individual; Inflammatory; Inflammatory Response; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Lead; Ligands; MHC Class II Genes; Mass Spectrum Analysis; Mediating; Pathogenesis; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Post-Translational Protein Processing; Process; Proinsulin; Proteins; Proteolysis; Reagent; Research Priority; Residual state; Role; Secretory Vesicles; Source; Specificity; Structure of beta Cell of islet; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Transplantation; Work; autoreactive T cell; base; diabetic; diabetogenic; disorder prevention; human disease; human study; human subject; islet; islet amyloid polypeptide; novel; protein aminoacid sequence; public health relevance; yeast two hybrid system

 DESCRIPTION (provided by applicant): Investigating the antigenic ligands for autoreactive T cells has been a high priority research goal for T1D because identification of peptide targets will lead to a better understanding of how this autoimmune disease develops and how it might be regulated. Insulin has long been considered to be the most important beta cell autoantigen in type 1 diabetes (T1D), but we recently discovered that two other secretory granule proteins, chromogranin A (ChgA) and islet amyloid polypeptide (IAPP), are also the source of antigenic peptides for autoreactive CD4 T cells. The goals of the first five-year period of this project were focused on identification of antigens for a panel of pathogenic CD4 T cell clones, whether post-translational modification (PTM) was involved in peptide antigenicity, and whether antigenic peptides could be used in strategies to induce antigen-specific tolerance. Our progress with all of these objectives has been significant, but our most notable discovery has been the identification of a novel PTM occurring in islet β-cells and leading to the formation of hybrid peptides between fragments of insulin and sequences from other secretory granule protein cleavage products. Two of these hybrid insulin peptides (HIPs) have been demonstrated to be highly antigenic for different subsets of T cell clones from our panel, those that are ChgA-reactive and another set that is IAPP-reactive. Our hypothesis in the second five-year period of this project is that the target ligands for autoreactive CD4 T cells are HIPs. Our aims will be to (1) define the role of HIP-reactive CD4 T cells in pathogenesis versus prevention of disease in NOD mice; (2) establish the presence of hybrid peptides in human islet beta cells; and (3) detect and characterize HIP-reactive T cells in human T1D patients and controls. The long-term translational significance of these studies lies in the potential for new reagents that could specifically detect autoreactive T cells as biomarkers of autoimmune diabetes in humans and/or serve as peptides for induction of antigen-specific tolerance.

 描述（由申请人提供）：研究自身反应性 T 细胞的抗原配体一直是 T1D 的一个高度优先的研究目标，因为肽靶标的鉴定将有助于 有助于更好地了解这种自身免疫性疾病如何发展以及如何对其进行调节。长期以来，胰岛素一直被认为是 1 型糖尿病 (T1D) 中最重要的 β 细胞自身抗原，但我们最近发现另外两种分泌颗粒蛋白，嗜铬粒蛋白 A (ChgA) 和胰岛淀粉样多肽 (IAPP)，也是自身反应性 CD4 T 细胞抗原肽的来源。该项目第一个五年期的目标是 重点关注一组致病性 CD4 T 细胞克隆的抗原鉴定、翻译后修饰 (PTM) 是否与肽抗原性有关，以及抗原肽是否可用于诱导抗原特异性耐受的策略。我们在所有这些目标上取得的进展都是重大的，但我们最引人注目的发现是发现了胰岛 β 细胞中发生的新型 PTM，并导致胰岛素片段和其他分泌颗粒蛋白裂解产物的序列之间形成杂合肽。其中两种混合胰岛素肽 (HIP) 已被证明对我们小组中的不同 T 细胞克隆子集具有高度抗原性，其中一组是 ChgA 反应性的，另一组是 IAPP 反应性的。我们在该项目第二个五年期间的假设是，自身反应性 CD4 T 细胞的靶配体是 HIP。我们的目标是 (1) 明确 HIP 反应性 CD4 T 细胞在 NOD 小鼠发病机制与疾病预防中的作用； (2) 确定人胰岛β细胞中存在杂合肽； (3) 检测并表征人类 T1D 患者和对照中的 HIP 反应性 T 细胞。这些研究的长期转化意义在于新试剂的潜力，这些新试剂可以特异性检测自身反应性 T 细胞作为人类自身免疫性糖尿病的生物标志物和/或作为诱导抗原特异性耐受的肽。