Abstract：
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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 TH2 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.
CONCLUSIONS: We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of TH2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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 TH2 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.
CONCLUSIONS: We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of TH2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.
摘要：
背景：嗜酸性粒细胞积聚是嗜酸性胃炎（EoG）的主要特征，并与其组织学诊断和病理有关。然而,多项临床试验表明，EoG内镜，尽管嗜酸性粒细胞完全耗尽,但非嗜酸性粒细胞的组织学和临床特征仍然持续存在.
目的：与安慰剂治疗的EoG患者相比，观察贝那利珠单抗诱导的嗜酸性粒细胞减少后胃T细胞组成和相关细胞因子水平。
方法：一组EoG患者接受12周治疗，使用3次贝那利珠单抗(抗IL-5受体α抗体，n=5）或安慰剂（n=4）来自参加最近2期贝那利珠单抗试验的受试者子集。在brefeldinA和莫能菌素的存在下，用佛波醇12,13-二丁酸酯（PDBU）和离子霉素刺激胃活检的单细胞悬浮液。将收获的细胞固定,染色,并通过流式细胞术分析T细胞群和相关细胞因子。
结果：贝那利珠单抗治疗后，而不是安慰剂，血液和胃嗜酸性粒细胞水平下降了16倍和10倍，分别。虽然组织学评分和特征显著下降，在内镜评分和特征方面未观察到变化.在用贝那利珠单抗完全消除嗜酸性粒细胞后，胃辅助T型2（Th2）细胞高3倍，与它们相关的IL-4，IL-5和IL-13的2型细胞因子产生增加了4倍，5.5折，和2.5倍，分别,与服用安慰剂的EoG患者相比。
结论：我们已经确定了一个推定的正反馈回路，其中嗜酸性粒细胞耗竭导致Th2细胞和衍生细胞因子的矛盾增加；这一发现表明了嗜酸性粒细胞耗竭作为嗜酸性粒细胞相关胃肠道疾病（EGID）的单一疗法的有限成功的解释。
目的：与安慰剂治疗的EoG患者相比，观察贝那利珠单抗诱导的嗜酸性粒细胞减少后胃T细胞组成和相关细胞因子水平。
方法：一组EoG患者接受12周治疗，使用3次贝那利珠单抗(抗IL-5受体α抗体，n=5）或安慰剂（n=4）来自参加最近2期贝那利珠单抗试验的受试者子集。在brefeldinA和莫能菌素的存在下，用佛波醇12,13-二丁酸酯（PDBU）和离子霉素刺激胃活检的单细胞悬浮液。将收获的细胞固定,染色,并通过流式细胞术分析T细胞群和相关细胞因子。
结果：贝那利珠单抗治疗后，而不是安慰剂，血液和胃嗜酸性粒细胞水平下降了16倍和10倍，分别。虽然组织学评分和特征显著下降，在内镜评分和特征方面未观察到变化.在用贝那利珠单抗完全消除嗜酸性粒细胞后，胃辅助T型2（Th2）细胞高3倍，与它们相关的IL-4，IL-5和IL-13的2型细胞因子产生增加了4倍，5.5折，和2.5倍，分别,与服用安慰剂的EoG患者相比。
结论：我们已经确定了一个推定的正反馈回路，其中嗜酸性粒细胞耗竭导致Th2细胞和衍生细胞因子的矛盾增加；这一发现表明了嗜酸性粒细胞耗竭作为嗜酸性粒细胞相关胃肠道疾病（EGID）的单一疗法的有限成功的解释。
