Insulin Specific T and B cells in Type 1 Diabetes

1 型糖尿病中的胰岛素特异性 T 细胞和 B 细胞

• 批准号: 9180031
• 负责人: John C Cambier
• 金额: $ 168.89万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180031
• 关键词: Affinity; Alleles; Amino Acids; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; B-insulin; Beta Cell; Binding; Biological Assay; Biological Markers; Blood; Blood typing procedure; CD19 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Culture Techniques; Cell Line; Cell Separation; Cells; Clinical; Cytometry; Development; Diabetes prevention; Disease; Disease Progression; First Degree Relative; Frequencies; Glycosylated hemoglobin A; Goals; HLA-DQ Antigens; HLA-DQ8 antigen; Histocompatibility Antigens Class II; Human; Immune; Immune system; Immunoglobulins; Immunologics; Immunology; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin-10; Islet Cell; Islets of Langerhans; Knowledge; Lead; Life; Link; Longitudinal Studies; Lymphocyte; Maintenance; Measures; Mediating; Metabolic; Natural History; Null Lymphocytes; OGTT; Oral; Organ; Organ Donor; Pancreas; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Play; Preparation; Prevention; Prevention trial; Proinsulin; Receptors, Antigen, B-Cell; Relapse; Research; Research Personnel; Risk; Role; Specificity; Spleen; Staining method; Stains; Study Subject; Symptoms; T cell response; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissues; Translating; adaptive immunity; anergy; biobank; cytokine; diabetes risk; high risk; human disease; insulin dependent diabetes mellitus onset; islet; lymph nodes; macrophage; peripheral blood; prospective; receptor; skills; subcutaneous

Project Summary The adaptive immune response to islet antigens, especially proinsulin, plays a central role in type 1 diabetes (T1D) development and pathology, with both T and B cells contributing to disease. Numerous large-scale prevention trials, mainly using preparations of insulin (subcutaneous, oral, and intranasal) to induce tolerance and delay the onset of clinical symptoms, have been unsuccessful. There exists the need to (1) study the autoimmune pathogenesis within the target organ of human T1D and (2) translate immunologic phenotypes from the islets to the blood of at risk subjects. We have recently identified proinsulin-reactive T cells from the islets of a T1D organ donor with a specific T cell receptor (TCR) responding to insulin B chain amino acids 9- 23 presented by HLA-DQ8 when transfected into a TCR null cell line. This T cell also responds to dispersed whole human islets, thus linking insulin B:9-23 T cell reactivity to human disease pathogenesis. Insulin B:9-23 specific CD4 T cells are present in the peripheral blood of new-onset T1D subjects. High affinity insulin- reactive B cells are found in the peripheral blood of healthy subjects, and these cells are restricted to the anergic B cell compartment (BND) and thus are antigen unresponsive. Importantly, in new-onset T1D patients and some first-degree relatives (FDRs) carrying high-risk HLA alleles, these B cells lose anergy. These findings lead us to hypothesize that insulin specific T and B cells undergo cognate interactions prior to the development of overt disease and concentrate in the pancreatic islets and lymph nodes where they propagate disease. This hypothesis will be tested in two specific aims. Utilizing the network for pancreatic organ donors (nPOD), Aim 1 focuses on defining antigen specificity, phenotypes and function of islet reactive immune cells from spleen and islets of organ donors with recent onset T1D. Aim 2 is a longitudinal study of at risk subjects with ≥2 islet autoantibodies and HLA-DQ-DR matched autoantibody negative first degree relatives from the TrialNet Pathway to Prevention (PTP) Living Biobank (previously referred to as the Natural History Study) measuring functional insulin specific T cell responses, enumerating insulin binding B cells, and characterizing insulin autoantibodies for antigen affinity and subtypes. The proposed studies will advance our long-term goal of bridging the gap of knowledge between the target organ and blood for biomarkers of disease progression and ultimately T1D prevention with enhanced understanding of disease pathogenesis.

项目概要 对胰岛抗原（尤其是胰岛素原）的适应性免疫反应在 1 型糖尿病中发挥着核心作用 (T1D) 发育和病理学，T 细胞和 B 细胞都会导致疾病。众多大型 预防试验，主要使用胰岛素制剂（皮下、口服和鼻内）诱导耐受 并延缓临床症状的出现，均未成功。需要（1）研究 人类 T1D 靶器官内的自身免疫发病机制和 (2) 转化免疫表型 从胰岛到高危受试者的血液。我们最近从以下细胞中鉴定出了胰岛素原反应性 T 细胞 T1D 器官捐献者的胰岛具有响应胰岛素 B 链氨基酸 9- 的特定 T 细胞受体 (TCR) 23 当转染至 TCR 无效细胞系时由 HLA-DQ8 呈递。该 T 细胞还对分散的 整个人类胰岛，从而将胰岛素 B:9-23 T 细胞反应性与人类疾病发病机制联系起来。胰岛素B：9-23 新发 T1D 受试者的外周血中存在特异性 CD4 T 细胞。高亲和力胰岛素- 反应性 B 细胞存在于健康受试者的外周血中，这些细胞仅限于 B 细胞区室 (BND) 无能，因此对抗原无反应。重要的是，对于新发 T1D 患者 以及一些携带高风险 HLA 等位基因的一级亲属 (FDR)，这些 B 细胞会失去反应性。这些 研究结果使我们推测胰岛素特异性 T 细胞和 B 细胞在 出现明显的疾病并集中在胰岛和淋巴结中并在那里传播 疾病。该假设将在两个具体目标中得到检验。利用胰腺器官捐赠者网络 (nPOD)，目标 1 侧重于定义胰岛反应性免疫细胞的抗原特异性、表型和功能 来自最近发病的 T1D 器官捐献者的脾脏和胰岛。目标 2 是对高危受试者的纵向研究 具有≥2个胰岛自身抗体且HLA-DQ-DR匹配的自身抗体阴性的一级亲属 TrialNet 预防途径 (PTP) 活体生物库（以前称为自然历史研究） 测量功能性胰岛素特异性 T 细胞反应，计数胰岛素结合 B 细胞，并表征 胰岛素自身抗体的抗原亲和力和亚型。拟议的研究将推进我们的长期目标 弥合目标器官和血液之间关于疾病进展生物标志物的知识差距 并最终通过增强对疾病发病机制的了解来预防 T1D。