Development of T-cell receptor repertoire profiling as a diagnostic for T1D

开发 T 细胞受体谱分析作为 T1D 诊断

• 批准号: 7998971
• 负责人: Robert J Livingston
• 金额: $ 33.28万
• 依托单位: ADAPTIVE BIOTECHNOLOGIES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998971
• 关键词: Adverse effects; Alleles; Autoantibodies; Autoimmune Process; Autoimmunity; Beta Cell; Biological; Biological Assay; Biological Markers; Biological Preservation; Blood specimen; CD8B1 gene; Cell physiology; Cells; DNA Sequence Rearrangement; Data; Development; Diagnosis; Diagnostic; Disease; Early treatment; Event; Frequencies; Goals; Gold; Immune; Immune System Diseases; Immune Tolerance; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Legal patent; Measures; Memory; Methods; Molecular; Molecular Profiling; Pancreas; Patients; Pattern; Pharmacologic Substance; Phase; Process; Production; Quality Control; Relative (related person); Research Design; Severities; Signal Transduction; Staging; Symptoms; T memory cell; T-Cell Receptor; T-Cell Receptor Genes; Technology; Time; Variant; blood glucose regulation; case control; design; high risk; insulin dependent diabetes mellitus onset; internal control; public health relevance; receptor; tool

DESCRIPTION (provided by applicant): The goal of this Phase I project is the identification of a molecular signature in the T-cell receptor repertoire of early-stage Type 1 Diabetes (T1D) patients that distinguishes these patients from controls. At present, immunomodulatory therapies have not proven useful for treatment of T1D, largely because of adverse side effects and also because pancreatic function has already been compromised by the time symptoms present. A diagnostic product that could detect the very earliest events in breaking tolerance, such as the development of a signature pattern in the repertoire of T-cell receptor (TCR) sequences, would allow for early intervention in high-risk individuals, potentially providing an opportunity for preservation of islet cell function and natural insulin production. Herein, we propose to commercialize our high-throughput TCR( sequencing assay to identify signals in the TCR( sequence repertoire that are indicative of loss of islet cell function. The ability to simultaneously sequence millions of individual T-cell receptor genes in single individuals provides, for the first time, the potential to directly observe disease-associated changes in the immune repertoire, the very set of receptors that evolves as T1D moves from initiation to progressive beta cell destruction. The utility of this signature as a diagnostic tool could expand treatment options for T1D by identifying individuals in the very earliest stages of disease, when therapy and treatment could be most effective. PUBLIC HEALTH RELEVANCE: Type 1 Diabetes (T1D) is usually diagnosed when symptoms present, a stage of disease in which autoimmunity has caused the loss of islet cell function. We propose to identify a signature pattern in the repertoire of T-cell receptor (TCR) sequences that could serve as a diagnostic product to detect the very earliest stage of disease. A diagnosis at earlier stages would allow for early intervention in high-risk individuals, potentially providing an opportunity for preservation of islet cell function and natural insulin production.

描述（由申请人提供）：该I期项目的目标是鉴定早期1型糖尿病（T1D）患者T细胞受体库中的分子特征，以区分这些患者与对照组。目前，免疫调节疗法尚未被证明对T1D的治疗有用，主要是因为不良副作用，还因为胰腺功能已经在症状出现时受到损害。一种诊断产品，可以检测破坏耐受性的最早事件，例如T细胞受体（TCR）序列库中的签名模式的发展，将允许对高危个体进行早期干预，可能为胰岛细胞功能和天然胰岛素生产的保护提供机会。 在此，我们提出将我们的高通量TCR（测序测定）商业化，以鉴定TCR（序列库）中指示胰岛细胞功能丧失的信号。在单个个体中同时测序数百万个单个T细胞受体基因的能力首次提供了直接观察免疫库中疾病相关变化的可能性，这组受体随着T1D从启动到进行性β细胞破坏而演变。这种特征作为诊断工具的实用性可以通过在疾病的最早阶段识别个体来扩展T1D的治疗选择，此时治疗和治疗可能是最有效的。 公共卫生关系：1型糖尿病（T1D）通常在出现症状时被诊断出来，这是一种自身免疫性导致胰岛细胞功能丧失的疾病阶段。我们建议在T细胞受体（TCR）序列库中识别一种签名模式，该模式可以作为诊断产品来检测疾病的最早阶段。在早期阶段的诊断将允许对高危个体进行早期干预，可能为胰岛细胞功能和天然胰岛素产生的保护提供机会。