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

描述(由申请人提供)：这个第一阶段项目的目标是识别早期1型糖尿病(T1D)患者T细胞受体谱系中的分子特征，将这些患者与对照组区分开来。目前，免疫调节疗法尚未被证明对治疗T1D有效，这主要是因为副作用，也因为出现症状的时间已经损害了胰腺功能。一种可以检测到打破耐受性的最早事件的诊断产品，例如在T细胞受体(TCR)序列库中形成标志性模式，将允许对高危个体进行早期干预，可能为保存胰岛细胞功能和自然胰岛素产生提供机会。 在此，我们建议将我们的高通量TCR(测序分析)商业化，以识别TCR(序列谱系)中指示胰岛细胞功能丧失的信号。在单个个体中同时对数百万个单独的T细胞受体基因进行测序的能力首次提供了直接观察免疫谱系中与疾病相关的变化的可能性，免疫谱系正是随着T1D从起始到渐进的β细胞破坏而进化的受体集。这一特征作为一种诊断工具的用途，可以通过在疾病的最早阶段识别个体，从而扩大T1D的治疗选择，此时的治疗和治疗可能最有效。 公共卫生相关性：1型糖尿病(T1D)通常在症状出现时被诊断出来，这是一种自身免疫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)序列库中识别一种特征模式，该模式可以作为一种诊断产品来检测疾病的最早阶段。早期诊断将允许对高危个体进行早期干预，可能为保留胰岛细胞功能和自然胰岛素产生提供机会。

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.