Human islet-derived, islet-reactive T cells from subjects with Type 1 diabetes

来自 1 型糖尿病患者的人胰岛衍生的胰岛反应性 T 细胞

• 批准号: 9280795
• 负责人: SALLY Choate KENT
• 金额: $ 20.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280795
• 关键词: Activities of Daily Living; Antigen-Presenting Cells; Autoantigens; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Biological Assay; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Communication; Cell Line; Cell surface; Cells; Childhood; Cities; Clinical Trials; Clone Cells; Coupled; Diabetes Mellitus; Disease; Engineering; Epitopes; Future; Goals; Histology; Human; Immunohistochemistry; Immunotherapy; In Situ; Inbred NOD Mice; Individual; Infiltration; Innate Immune System; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Left; Lymphocytic Infiltrate; Massachusetts; Methods; Modeling; Modification; Organ Donor; Pancreas; Pathogenesis; Peptides; Peripheral; Phenotype; Post-Translational Protein Processing; Prevention; Proinsulin; Proteins; Reagent; Receptor Cell; Recovery; Regulatory T-Lymphocyte; Reporting; Research Design; Research Personnel; Risk; Rodent Model; Sampling; T-Cell Receptor; T-Lymphocyte; Translating; Translations; United States; Universities; Ursidae Family; autoreactive T cell; autoreactivity; cell type; cytokine; cytotoxicity; design; disorder risk; human disease; human subject; humanized mouse; immunopathology; insight; islet; lymph nodes; medical schools; mouse model; peripheral blood; programs; success; tool

PROJECT SUMMARY/ABSTRACT Understanding the autoimmune response in human type 1 diabetes (T1D) is crucial for the design of successful immunotherapies for those at-risk for the disease as well as for those with established disease. While studies of rodent models of have greatly instructed us on the autoimmune process, the translation of successful therapies and prevention studies in the rodent models to human clinical trials has been far less successful. While we know much information concerning islet infiltrating T cells in the rodent models and islet infiltrates in humans with T1D by histology and immunohistochemistry, we previously have not had the opportunity to isolate directly the lymphocytic infiltrate from human with T1D for repertoire analysis and functional capacity. We have received islet isolations from 7 individuals with T1D and have grown or sorted directly out of the islets, 95 CD4 and CD* T cell lines. We have demonstrated the reactivity and HLA restriction of 4 CD4+ T cell lines and 3 CD8+ T cells lines (multiple reactivities are represented). The purpose of this proposal is to assay each T cell line for reactivity to whole normal islets, whole islet proteins, known islet- associated peptide targets of autoreactive T cells, to peptides derived from islet proteins that bear post- translational modifications, to define their HLA restriction, and define their effector functions. These islet- infiltrating T cells will be vital tools/reagents for investigators in the field to study the function of islet-infiltrating T cells in humanized mouse models of T1D, T cell receptor repertoire, to preserve autoreactive T cell receptors for future studies, in functional assays of autoreactive T cell interactions with T regulatory cells, B cell, antigen presenting cells and the innate immune system. Finally, these studies will inform investigators in the design of successful immunotherapies for those at-risk for T1D and especially for those with established T1D.

项目概要/摘要 了解人类 1 型糖尿病 (T1D) 的自身免疫反应对于设计 为那些有患病风险以及已确诊疾病的人提供成功的免疫疗法。 虽然对啮齿动物模型的研究极大地指导了我们自身免疫过程，但 从啮齿动物模型到人体临床试验的成功治疗和预防研究要少得多 成功的。虽然我们知道很多有关啮齿动物模型和胰岛中胰岛浸润 T 细胞的信息 通过组织学和免疫组织化学，我们以前没有发现过 T1D 患者的浸润情况 有机会直接从 T1D 患者中分离淋巴细胞浸润以进行谱分析 功能能力。我们已收到 7 名 T1D 患者的胰岛分离物，并进行了培养或分类 直接从胰岛中提取 95 个 CD4 和 CD* T 细胞系。我们已经证明了反应性和 HLA 限制 4 个 CD4+ T 细胞系和 3 个 CD8+ T 细胞系（表示多种反应性）。这样做的目的 建议检测每个 T 细胞系对整个正常胰岛、整个胰岛蛋白、已知胰岛的反应性 自身反应性 T 细胞的相关肽靶标，以及源自胰岛蛋白的肽，这些肽具有后 翻译修饰，以定义其 HLA 限制，并定义其效应器功能。这些小岛—— 浸润性T细胞将成为该领域研究人员研究胰岛浸润功能的重要工具/试剂 T1D 人源化小鼠模型中的 T 细胞、T 细胞受体库，以保留自身反应性 T 细胞受体 用于未来研究，用于自身反应性 T 细胞与 T 调节细胞、B 细胞、抗原相互作用的功能测定 呈现细胞和先天免疫系统。最后，这些研究将为研究人员设计 对于那些有 T1D 风险的人，特别是那些已确诊的 T1D 患者，成功进行免疫疗法。

项目成果

Corrigendum: Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

勘误表：1 型糖尿病人类捐献者胰岛浸润 T 细胞自身抗原特异性的分析。

• DOI: 10.1038/nm0817-1004a
• 发表时间: 2017
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Babon,JennyAurielleB;DeNicola,MeganE;Blodgett,DavidM;Crèvecoeur,Inne;Buttrick,ThomasS;Maehr,René;Bottino,Rita;Naji,Ali;Kaddis,John;Elyaman,Wassim;James,EddieA;Haliyur,Rachana;Brissova,Marcela;Overbergh,Lut;Mathieu,Chanta
• 通讯作者: Mathieu,Chanta