Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.

中文翻译：

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药物代谢组学应用于低剂量白介素 2 治疗肌萎缩侧索硬化症


肌萎缩侧索硬化症（ALS）是一种破坏性的运动神经元疾病。调节性 T 淋巴细胞 (Treg) 的免疫抑制功能在 ALS 中受损，并与疾病进展相关。 2a 期 IMODALS 试验报告称，在服用低剂量 (ld) 白细胞介素 2 (IL-2) 后，ALS 患者的 Treg 数量有所增加。我们提出了一种药物代谢组学方法来破译 ld-IL-2 治疗患者中发生的代谢改变及其与 Treg 反应的关系。在第 D1、D64 和 D85 天测定接受 2 MIU IL-2 的患者 (n = 12) 和接受安慰剂的患者 (n = 12) 的血液代谢组学特征。我们区分了治疗组的三个时间点（平均错误率为 42%）。在重要的代谢物中，犬尿氨酸在 D1 和 D64 之间增加，随后在 D85 减少。正如 D1 代谢组预测的那样，Treg 数量从 D1 到 D64 的增加百分比与观察值高度相关。这项研究为 ld-IL-2 在 ALS 中的作用的代谢表征提供了概念证明。这些数据可以代表个性化医疗方法的进展，并将药物代谢组学作为补充药物表征的基因组和转录数据的关键工具，从而导致系统药理学。