Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis.
Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis.
复制标题
低剂量白细胞介素 2 用于治疗中度至重度溃疡性结肠炎。
DOI：
10.1053/j.gastro.2023.03.230
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发表时间：
2023
期刊：
影响因子：
29.4
通讯作者：
Snapper,ScottB
中科院分区：
文献类型：
--
作者：
Allegretti,JessicaR;Mitsialis,Vanessa;Canavan,JamesB;Low-DoseIL2UCStudyGroup;Snapper,ScottB
溃疡性结肠炎（UC）代表人类结肠的一种炎症性疾病，据信部分是由宿主免疫系统失调介导的，包括可能不充分的粘膜Treg反应。1，2低剂量（LD）白细胞介素-2（IL-2）已显示在小鼠模型3 -6以及人类试验7 -9中扩增外周T细胞（TCLs）并改善各种炎性疾病。此外，我们先前已经报道了LD IL-2治疗后人源化小鼠结肠炎的改善10。我们假设LD IL-2介导的TcR扩增可能抑制UC疾病，并提供一种新的治疗方法。在此，我们评估LD IL-2在UC患者中是否安全、是否能扩大THBVDNA并影响潜在的免疫机制。我们在中重度UC患者中进行了一项每日皮下注射LD IL-2（Proleukin®）的开放标签1b/2a期8周诱导试验。共入组了26例活动性疾病（总马约评分6-10）和对≥ 1种UC治疗无效的成人患者（表S1）。主要目的是评估LD IL-2的安全性和耐受性，并通过3+ 3设计确定最大耐受剂量（MTD），其中3个剂量递增队列为：0.3 × 106 IU/m2/天（剂量A）、1 × 106 IU/m2/天（剂量B）（GvHD 8中的MTD）或1.5 × 106 IU/m2/天（剂量C），一旦确定，则在MTD时再招募10名受试者。次要结局包括通过临床应答（第8周时总马约评分降低≥ 3或≥ 30%）和临床缓解（总马约评分≤ 2，单个分项评分不超过1，包括第8周马约内镜评分[MES]）测定的疗效。在治疗前和第8周进行软式乙状结肠镜检查。每1-2周评估一次实验室和临床参数。对外周血粘膜样品进行流式细胞术以评估Treg和常规T细胞（Tcon）群体以及活化状态的变化。
Ulcerative colitis (UC) represents an inflammatory condition of the human colon believed in part to be mediated by dysregulation of the host immune system including potentially inadequate mucosal Treg responses. 1, 2 Low dose (LD) interleukin-2 (IL-2) has been shown to expand peripheral Tregs (Tregs) and ameliorate various inflammatory diseases in mouse models3-6 as well as in human trials7-9. Additionally, we have previously reported amelioration of colitis in humanized mice following LD IL-2 treatment10. We hypothesize that LD IL-2-mediated expansion of Tregs may suppress disease in UC and provide a novel treatment approach. Here we assess whether LD IL-2 is safe in UC patients, expands Tregs, and affects underlying immune mechanisms.We conducted an open-label phase 1b/2a 8-week induction trial of daily subcutaneous LD IL-2 (Proleukin®), in patients with moderate-to-severe UC. A total of 26 adult patients with active disease (total Mayo Score 6-10) and failure of response to≥ 1 UC therapy were enrolled (Table S1). The primary objectives were assessment of safety and tolerability of LD IL-2 and determination of the maximum tolerated dose (MTD) via a 3+ 3 design with three dose-escalation cohorts: 0.3 x106 IU/m2/day (Dose A), 1x106 IU/m2/day (Dose B)(MTD in GvHD8) or 1.5 x106 IU/m2/day (Dose C) with an additional 10 enrolled at the MTD, once determined. Secondary outcomes included determination of efficacy as measured by clinical response (decrease in total Mayo score of≥ 3 or≥ 30% at week 8) and clinical remission (a total Mayo score of≤ 2, with no individual sub-score exceeding 1, including the week 8 Mayo endoscopic score [MES]). Flexible sigmoidoscopy was performed before treatment and at week 8. Laboratory and clinical parameters were assessed every 1-2 weeks. Flow cytometry was performed on peripheral blood mucosal samples to assess changes in Treg and conventional T cell (Tcon) populations as well as activation states.