评估对 gluten challenge 的反应：一项随机、双盲、2 剂量 gluten challenge 试验。
Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial.
机构信息
Center for Celiac Research and Treatment, Massachusetts General Hospital, Boston, Massachusetts; Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts.
Celiac Disease Research Program, Harvard Medical School, Boston, Massachusetts; Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts; Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
出版信息
Gastroenterology. 2021 Feb;160(3):720-733.e8. doi: 10.1053/j.gastro.2020.10.040. Epub 2020 Oct 29.
BACKGROUND & AIMS: Gluten challenge is used to diagnose celiac disease (CeD) and for clinical research. Sustained gluten exposure reliably induces histologic changes but is burdensome. We investigated the relative abilities of multiple biomarkers to assess disease activity induced by 2 gluten doses, and aimed to identify biomarkers to supplement or replace histology.
METHODS
In this randomized, double-blind, 2-dose gluten-challenge trial conducted in 2 US centers (Boston, MA), 14 adults with biopsy-proven CeD were randomized to 3 g or 10 g gluten/d for 14 days. The study was powered to detect changes in villous height to crypt depth, and stopped at planned interim analysis on reaching this end point. Additional end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with HLA-DQ2-gluten tetramers and enzyme-linked immune absorbent spot, gut-homing CD8 T cells, interleukin-2, symptoms, video capsule endoscopy, intraepithelial leukocytes, and tissue multiplex immunofluorescence.
RESULTS
All assessments showed changes with gluten challenge. However, time to maximal change, change magnitude, and gluten dose-response relationship varied. Villous height to crypt depth, video capsule endoscopy enteropathy score, enzyme-linked immune absorbent spot, gut-homing CD8 T cells, intraepithelial leukocyte counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten only; symptoms were significant at 3 g. Symptoms and plasma interleukin-2 levels increased significantly or near significantly at both doses. Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure.
CONCLUSIONS
Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion. This work provides a preliminary framework for rational design of gluten challenge for CeD research. ClinicalTrials.gov number, NCT03409796.
背景与目的
谷蛋白激发试验用于诊断乳糜泻（CeD）和临床研究。持续的谷蛋白暴露能可靠地诱导组织学变化，但负担沉重。我们研究了多种生物标志物评估两种谷蛋白剂量诱导的疾病活动的相对能力，并旨在确定补充或替代组织学的生物标志物。
方法
在这两项在美国两个中心（马萨诸塞州波士顿）进行的随机、双盲、两剂量谷蛋白激发试验中，14 名经活检证实患有 CeD 的成年人被随机分配到 3 g 或 10 g/d 的谷蛋白剂量，持续 14 天。该研究具有检测绒毛高度到隐窝深度变化的能力，并在达到这一终点时按计划进行中期分析。其他终点包括使用 HLA-DQ2-谷蛋白四聚体和酶联免疫吸附斑点、肠道归巢 CD8 T 细胞、白细胞介素-2、症状、视频胶囊内镜、上皮内白细胞和组织多重免疫荧光分析的谷蛋白特异性 CD4 T 细胞分析。
结果
所有评估均显示谷蛋白激发后发生变化。然而，最大变化时间、变化幅度和谷蛋白剂量反应关系存在差异。仅 10 g 谷蛋白组的绒毛高度到隐窝深度、视频胶囊内镜肠病评分、酶联免疫吸附斑点、肠道归巢 CD8 T 细胞、上皮内白细胞计数和 HLA-DQ2 限制性谷蛋白特异性 CD4 T 细胞从基线开始有显著变化；3 g 组的症状有显著变化。两种剂量下，症状和血浆白细胞介素-2 水平均显著或接近显著增加。白细胞介素-2似乎是急性谷蛋白暴露最早、最敏感的标志物。
结论
现代生物标志物对谷蛋白暴露敏感且有反应性，可能允许进行侵入性更小、剂量更低、持续时间更短的谷蛋白摄入。这项工作为乳糜泻研究中的谷蛋白激发提供了初步框架。临床试验注册号，NCT03409796。
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