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
基本信息
- 批准号:9180031
- 负责人:
- 金额:$ 168.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffinityAllelesAmino AcidsAntibodiesAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityB-LymphocytesB-insulinBeta CellBindingBiological AssayBiological MarkersBloodBlood typing procedureCD19 geneCD4 Positive T LymphocytesCD8B1 geneCell Culture TechniquesCell LineCell SeparationCellsClinicalCytometryDevelopmentDiabetes preventionDiseaseDisease ProgressionFirst Degree RelativeFrequenciesGlycosylated hemoglobin AGoalsHLA-DQ AntigensHLA-DQ8 antigenHistocompatibility Antigens Class IIHumanImmuneImmune systemImmunoglobulinsImmunologicsImmunologyInsulinInsulin-Dependent Diabetes MellitusInterferon Type IIInterleukin-10Islet CellIslets of LangerhansKnowledgeLeadLifeLinkLongitudinal StudiesLymphocyteMaintenanceMeasuresMediatingMetabolicNatural HistoryNull LymphocytesOGTTOralOrganOrgan DonorPancreasPathogenesisPathologyPathway interactionsPatientsPeptidesPhenotypePlayPreparationPreventionPrevention trialProinsulinReceptors, Antigen, B-CellRelapseResearchResearch PersonnelRiskRoleSpecificitySpleenStaining methodStainsStudy SubjectSymptomsT cell responseT-Cell DevelopmentT-Cell ReceptorT-LymphocyteTestingTimeTissuesTranslatingadaptive immunityanergybiobankcytokinediabetes riskhigh riskhuman diseaseinsulin dependent diabetes mellitus onsetisletlymph nodesmacrophageperipheral bloodprospectivereceptorskillssubcutaneous
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John C Cambier其他文献
Src-family kinases in B-cell development and signaling
B 细胞发育和信号转导中的 Src 家族激酶
- DOI:
10.1038/sj.onc.1208075 - 发表时间:
2004-10-18 - 期刊:
- 影响因子:7.300
- 作者:
Stephen B Gauld;John C Cambier - 通讯作者:
John C Cambier
John C Cambier的其他文献
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{{ truncateString('John C Cambier', 18)}}的其他基金
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
- 批准号:
9568080 - 财政年份:2016
- 资助金额:
$ 168.89万 - 项目类别:
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
- 批准号:
9121221 - 财政年份:2016
- 资助金额:
$ 168.89万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
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8282484 - 财政年份:2012
- 资助金额:
$ 168.89万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
- 批准号:
8519291 - 财政年份:2012
- 资助金额:
$ 168.89万 - 项目类别:
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