Quantitative measurement of T1D risk through molecular signature analysis

描述（由申请人提供）：成功延迟或预防1型糖尿病（T1 D）将在很大程度上取决于在具有高风险主要组织相容性复合体等位基因和/或胰岛细胞自身抗体（AA）滴度的个体中区分将进展为T1 D的个体。为了实现这一目标，我们已经开发并应用了一种灵敏的生物测定法，该生物测定法测量血清或血浆对良好控制的“报告者”外周血单核细胞（PBMC）群体中诱导的转录物水平的影响。通过这种方法，我们已经定义了一个最近发作（RO）T1 D签名，其中包括由白细胞介素-1调节的基因，白细胞介素-1是一种细胞因子，在体外诱导胰腺细胞凋亡并共同刺激T细胞。这种反应通过阻断培养物中的IL-1受体来调节，并且与由无关的健康对照、长期T1 D患者或患有其他疾病的患者的样品诱导的反应不同。到目前为止，我们已经检查了9个T1 D进展者的纵向样本;在所有情况下，RO T1 D特征在发病前都很明显。重要的是，在3/3的病例中检测到该特征，其中样品在AA形成之前可用。我们的数据支持这样的假设，即与对胰腺细胞的自身免疫相关的稀释的细胞因子环境足以诱导独特的T1 D特异性转录谱;该特征反映了主动的自身免疫，是疾病特异性的，并且可以改善AA以外的疾病预测。为了响应项目公告“对PAR-11-350的回应：使用选定的1型糖尿病临床研究（DP 3）的生物样本进行研究”，我们提出了这项合作、多中心研究，其中将仔细研究以下目标，以完善这种机制信息生物标志物，并确定其预测潜力和效用：1）将特征定义为T1 D进展分期的定量早期生物标志物。 2)定义T1 D特征的疾病特异性。

DESCRIPTION (provided by applicant): Successfully delaying or preventing type 1 diabetes (T1D) will depend heavily on distinguishing those individuals that will progress to T1D among those individuals possessing high risk major histocompatibility complex alleles and/or titers for islet cell auto-antibodies (AA). Towards this goal, we have developed and applied a sensitive bioassay that measures the effect of serum or plasma on induced transcript levels in a well- controlled "reporter" peripheral blood mononuclear cell (PBMC) population. With this approach we have defined a recent onset (RO) T1D signature that includes genes regulated by interleukin-1, a cytokine that induces pancreatic ¿-cell apoptosis in vitro and co-stimulates T-cells. This response is modulated by blocking IL-1 receptor in cultures and is distinct from that induced by samples of unrelated healthy controls, long- standing T1D patients, or patients possessing other diseases. So far, we have examined longitudinal samples of 9 progressors to T1D; in all cases the RO T1D signature was evident prior to onset. Importantly, this signature was detected in 3/3 cases where samples were available prior to AA development. Our data support the hypothesis that the dilute cytokine milieu associated with autoimmunity towards the pancreatic ¿-cells is sufficient to induce a unique T1D-specific transcriptional profile; this signature reflects active autoimmunity, is disease specific, and may improve disease prediction beyond AA. In response to Program Announcement " Response to PAR-11-350: Research Using Biosamples From Selected Type 1 Diabetes Clinical Studies (DP3)" we propose this collaborative, multicenter study where the following aims will be perused to refine this mechanistically informative biomarker and define its predictive potential and utility: 1) Define the signature as a quantitative early biomarker for staging T1D progression. 2) Define disease-specificity of the T1D-signature.