CD8 T Cell Reactivity to IGRP as an Autoimmunity Marker in Type 1 Diabetes

CD8 T 细胞对 IGRP 的反应作为 1 型糖尿病的自身免疫标志物

• 批准号: 7295806
• 负责人: Teresa P DiLorenzo
• 金额: $ 18.55万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295806
• 关键词: Age; Alleles; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Beta Cell; Binding; Biological Models; CD8B1 gene; Catalytic Domain; Cells; Characteristics; Class; Development; Diagnostic; Disease; Early Diagnosis; Epitope Mapping; Epitopes; Ethnic group; Gene Frequency; HLA A*0201 antigen; HLA-B*0702; HLA-Cw0304 antigen; Human; Inbred NOD Mice; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Language; Lead; Light; Major Histocompatibility Complex; Mediating; Monitor; Mus; Natural Killer Cells; Non obese; Participant; Patients; Peptides; Population; Proteins; Recurrence; Research Personnel; Risk; Standards of Weights and Measures; Study models; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; Translating; Week; Work; base; cell type; cytotoxic; diabetic; glucose metabolism; glucose-6-phosphatase; human disease; islet; mouse model; programs; response

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Studies of the nonobese diabetic (NOD) mouse model of the disease have shown that beta cell-cytotoxic CD8+ T cells are essential participants in the beta cell destruction that leads to T1D. CD8+ T cells are also suspected contributors to beta cell elimination in patients. We identified a peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) as the target of a prevalent population of pathogenic CD8+ T cells in NOD mice. In light of the similarities between T1D in NOD mice and humans, we hypothesize that IGRP-reactive CD8+ T cells will be important contributors to beta cell eradication in T1D patients as they are in NOD mice. To begin to translate our findings to patients, we used NOD mice transgenic for the human class I MHC molecule HLA-A*0201 to identify HLA-A*0201-binding IGRP peptides targeted by T cells during the spontaneous development of T1D. Reactivities identified using islet-infiltrating T cells from unimmunized HLA-transgenic mice are both spontaneously occurring and disease-relevant. Thus, these peptides represent excellent candidates for exploration as targets of T cells in human T1D patients. While HLA-A*0201 is a common class I MHC molecule, elucidation of the IGRP peptides recognized in the context of other human class I molecules would allow wider coverage of the population in terms of those that could benefit from the development of peptide- based predictive, diagnostic, and therapeutic strategies. To this end, we have generated three new NOD strains expressing HLA-A*1101, HLA-B*0702, or HLA-Cw*0304. These HLA molecules are representative of three different HLA supertypes, while HLA-A*0201 is representative of yet a fourth. Coverage of the population can be approximately 90% when all four supertypes are targeted. We will isolate islet-infiltrating T cells from the HLA-transgenic mice and determine the IGRP peptides recognized in the context of the different HLA molecules. We will then test the hypothesis that the same peptides will be recognized by T cells from T1D patients. Given the importance of IGRP as a target of the autoimmune response in both standard and HLA-A*0201-transgenic NOD mice, we hypothesize that CD8+ T cell responses to IGRP will also serve as markers for beta cell-specific autoimmune activity in humans. Monitoring of these T cell responses may permit assessment of the immunological impact of intervention therapies and allow earlier detection of autoimmune activity than is currently possible. Relevance in lay language: The proposed work may lead to new tests to identify individuals at risk of developing T1D. Tests may also be developed to monitor destructive T cell activity in patients undergoing treatment, so that doctors will be able to know if the treatments are working.

描述（由申请人提供）：1型糖尿病（T1D）是一种以T细胞介导的胰岛细胞破坏为特征的自身免疫性疾病。对非肥胖糖尿病（NOD）小鼠模型的研究表明，β细胞-细胞毒性CD8+ T细胞是导致T1D的β细胞破坏的重要参与者。CD8+ T细胞也被怀疑是患者消除β细胞的贡献者。我们确定了一种来自胰岛特异性葡萄糖-6-磷酸酶催化亚基相关蛋白（IGRP）的肽，作为NOD小鼠中普遍存在的致病性CD8+ T细胞群的靶标。鉴于NOD小鼠和人类的T1D之间的相似性，我们假设igrp反应性CD8+ T细胞将在NOD小鼠中对T1D患者的β细胞根除起重要作用。为了将我们的研究结果转化为患者，我们使用NOD小鼠转基因人类I类MHC分子HLA-A*0201来鉴定T细胞在T1D自发发展过程中靶向的HLA-A*0201结合IGRP肽。使用未免疫hla转基因小鼠的胰岛浸润T细胞鉴定的反应性既自发发生，又与疾病相关。因此，这些肽是探索人类T1D患者T细胞靶点的绝佳候选者。虽然HLA-A*0201是一种常见的I类MHC分子，但在其他人类I类分子背景下识别的IGRP肽的阐明将允许更广泛的人群覆盖，因为这些人群可能受益于基于肽的预测、诊断和治疗策略的发展。为此，我们获得了三种新的NOD菌株，分别表达HLA-A*1101、HLA-B*0702和HLA-Cw*0304。这些HLA分子代表了三种不同的HLA超型，而HLA- a *0201代表了第四种。当所有四种超类型都被瞄准时，人口覆盖率可以达到大约90%。我们将从HLA转基因小鼠中分离胰岛浸润T细胞，并确定在不同HLA分子背景下识别的IGRP肽。然后，我们将测试相同的肽将被T1D患者的T细胞识别的假设。鉴于IGRP在标准小鼠和HLA-A*0201转基因NOD小鼠中作为自身免疫反应靶点的重要性，我们假设CD8+ T细胞对IGRP的反应也将作为人类β细胞特异性自身免疫活性的标记物。监测这些T细胞反应可以评估干预疗法的免疫影响，并比目前可能的更早发现自身免疫活性。外行语言的相关性：拟议的工作可能会导致新的测试，以确定有患T1D风险的个体。还可以开发检测方法来监测正在接受治疗的患者体内破坏性T细胞的活性，这样医生就能知道治疗是否有效。