Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Division of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
J Allergy Clin Immunol. 2024 Nov;154(5):1325-1332.e2. doi: 10.1016/j.jaci.2024.07.018. Epub 2024 Jul 30.
Eosinophil accumulation is a main feature of eosinophilic gastritis (EoG) and is associated with its histologic diagnosis and pathology. However, a recent clinical trial has demonstrated that EoG endoscopic, noneosinophil histologic, and clinical features remain persistent despite complete eosinophil depletion.
Our aim was to examine gastric T-cell composition and associated cytokine levels of patients with EoG following benralizumab-induced eosinophil depletion versus following administration of placebo.
A cohort of subjects with EoG from a subset of subjects who participated in a recent phase 2 benralizumab trial was treated for 12 weeks with administration of 3 doses of benralizumab (anti-IL-5 receptor α antibody [n = 5]) or placebo (n = 4). Single-cell suspensions obtained by gastric biopsy were stimulated with phorbol 12,13-dibutyrate and ionomycin in the presence of brefeldin A and monensin. Harvested cells were fixed, stained, and analyzed by flow cytometry to examine T-cell populations and associated cytokines.
Following benralizumab treatment but not placebo, blood and gastric eosinophil levels decreased 16-fold and 10-fold, respectively. Whereas histologic score and features were significantly decreased, no change was observed in endoscopic score and features. Following complete eosinophil depletion with benralizumab, gastric T2 cell levels were 3-fold higher than the levels in the patients with EoG who were given placebo; and the levels of associated type 2 cytokine production of IL-4, IL-5, and IL-13 in the benralizumab-treated patients were, respectively, 4-, 5.5-, and 2.5-fold, higher than those in the placebo-treated patients.
We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of T2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.
嗜酸性粒细胞聚集是嗜酸性胃炎（EoG）的主要特征，与组织学诊断和病理学相关。然而，最近的一项临床试验表明，尽管嗜酸性粒细胞完全耗竭，EoG 的内镜、非嗜酸性粒细胞组织学和临床特征仍然持续存在。
我们的目的是检查接受 benralizumab 诱导的嗜酸性粒细胞耗竭与安慰剂治疗后 EoG 患者的胃 T 细胞组成和相关细胞因子水平。
从最近一项 2 期 benralizumab 试验的亚组受试者中选择了患有 EoG 的受试者队列，他们接受了 3 剂 benralizumab（抗 IL-5 受体 α 抗体[n=5]）或安慰剂（n=4）治疗 12 周。通过胃活检获得的单细胞悬液在存在布雷非德菌素 A 和莫能菌素的情况下用佛波醇 12,13-二丁酸酯和离子霉素刺激。收获的细胞固定、染色，并通过流式细胞术分析以检查 T 细胞群体和相关细胞因子。
在接受 benralizumab 治疗后，但在接受安慰剂治疗后，血液和胃嗜酸性粒细胞水平分别降低了 16 倍和 10 倍。尽管组织学评分和特征显著降低，但内镜评分和特征没有变化。在用 benralizumab 完全耗尽嗜酸性粒细胞后，胃 T2 细胞水平比给予安慰剂的 EoG 患者高 3 倍；并且 benralizumab 治疗患者的相关 2 型细胞因子产生的 IL-4、IL-5 和 IL-13 水平分别比安慰剂治疗患者高 4 倍、5.5 倍和 2.5 倍。
我们已经确定了一个假设的正反馈回路，即嗜酸性粒细胞耗竭导致 T2 细胞和衍生细胞因子水平的反常增加；这一发现为嗜酸性粒细胞耗竭作为嗜酸性粒细胞相关胃肠疾病的单一疗法的有限成功提供了一种解释。
