Song Dae Jin, Shim Mun Hee, Lee Nahyun, Yoo Young, Choung Ji Tae
Department of Pediatrics, Korea University College of Medicine, Seoul, Korea.
Environmental Health Center for Childhood Asthma, Korea University Anam Hospital, Seoul, Korea.
Allergy Asthma Immunol Res. 2017 Jul;9(4):360-367. doi: 10.4168/aair.2017.9.4.360.
Although the role of eosinophils in eosinophilic gastroenteritis (EGE) is not fully understood, they are believed to be a principal effector cell. Previous studies have demonstrated that eotaxin and its specific receptor, cysteine-cysteine chemokine receptor-3 (CCR3), play a central role in eosinophil trafficking into the gastrointestinal (GI) tract. Thus, we examined the targeting of CCR3 as a potential therapeutic intervention for EGE in a mouse model.
Eight- to 10-week-old BALB/c mice were intraperitoneally sensitized and intragastrically challenged with ovalbumin (OVA). Different groups of mice were administered either an anti-CCR3 antibody or a control IgG by intraperitoneal injection 1 hour before each OVA challenge. Eosinophilic inflammation in the intestinal mucosa, mucosal injury, and severity of diarrhea were compared between different groups at 1 hour after final OVA challenge.
Anti-CCR3 antibody reduced the number of eosinophils in peripheral blood and intestinal mucosa, but not in bone marrow. This reduction was associated with restoration of reduced villous crypt ratio, increased intestinal epithelial cell proliferation, and weight loss induced by OVA challenge. However, Anti-CCR3 antibody had no effect on the level of OVA specific immunoglobulin E (IgE) and the expression of critical chemokines or cytokines in eosinophil trafficking into the GI tract, such as eotaxin-1, interleukin (IL)-5, and IL-13.
Anti-CCR3 antibody significantly reduced the severity of eosinophilic inflammation, mucosal injury, and diarrhea in a mouse model of food allergen-induced GI eosinophilic inflammation. CCR3 may be a novel therapeutic target for treatment of EGE and other GI eosinophil-mediated diseases.
尽管嗜酸性粒细胞在嗜酸性粒细胞性胃肠炎（EGE）中的作用尚未完全明确，但它们被认为是主要的效应细胞。先前的研究表明，嗜酸性粒细胞趋化因子及其特异性受体，即半胱氨酸-半胱氨酸趋化因子受体-3（CCR3），在嗜酸性粒细胞向胃肠道（GI）的迁移中起核心作用。因此，我们在小鼠模型中研究了以CCR3为靶点作为EGE潜在治疗干预措施的效果。
8至10周龄的BALB/c小鼠经腹腔致敏，并用卵清蛋白（OVA）进行胃内激发。在每次OVA激发前1小时，通过腹腔注射给不同组的小鼠分别给予抗CCR3抗体或对照IgG。在末次OVA激发后1小时，比较不同组小鼠肠道黏膜中的嗜酸性粒细胞炎症、黏膜损伤及腹泻严重程度。
抗CCR3抗体减少了外周血和肠道黏膜中的嗜酸性粒细胞数量，但未减少骨髓中的嗜酸性粒细胞数量。这种减少与OVA激发所致的绒毛隐窝比值降低、肠道上皮细胞增殖增加及体重减轻的恢复有关。然而，抗CCR3抗体对OVA特异性免疫球蛋白E（IgE）水平以及嗜酸性粒细胞向胃肠道迁移过程中关键趋化因子或细胞因子（如嗜酸性粒细胞趋化因子-1、白细胞介素（IL）-5和IL-13）的表达没有影响。
在食物过敏原诱导的胃肠道嗜酸性粒细胞炎症小鼠模型中，抗CCR3抗体显著降低了嗜酸性粒细胞炎症、黏膜损伤及腹泻的严重程度。CCR3可能是治疗EGE及其他胃肠道嗜酸性粒细胞介导疾病的新治疗靶点。
