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Siglec-8 antibody reduces eosinophils and mast cells in a transgenic mouse model of eosinophilic gastroenteritis
Bradford A. Youngblood, … , Christopher Bebbington, Nenad Tomasevic
Bradford A. Youngblood, … , Christopher Bebbington, Nenad Tomasevic
Published August 29, 2019
Citation Information: JCI Insight. 2019;4(19):e126219. https://doi.org/10.1172/jci.insight.126219.
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Research Article Gastroenterology Therapeutics

Siglec-8 antibody reduces eosinophils and mast cells in a transgenic mouse model of eosinophilic gastroenteritis

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Abstract

Aberrant accumulation and activation of eosinophils and potentially mast cells (MCs) contribute to the pathogenesis of eosinophilic gastrointestinal diseases (EGIDs), including eosinophilic esophagitis (EoE), gastritis (EG), and gastroenteritis (EGE). Current treatment options, such as diet restriction and corticosteroids, have limited efficacy and are often inappropriate for chronic use. One promising new approach is to deplete eosinophils and inhibit MCs with a monoclonal antibody (mAb) against sialic acid–binding immunoglobulin-like lectin 8 (Siglec-8), an inhibitory receptor selectively expressed on MCs and eosinophils. Here, we characterize MCs and eosinophils from human EG and EoE biopsies using flow cytometry and evaluate the effects of an anti–Siglec-8 mAb using a potentially novel Siglec-8–transgenic mouse model in which EG/EGE was induced by ovalbumin sensitization and intragastric challenge. MCs and eosinophils were significantly increased and activated in human EG and EoE biopsies compared with healthy controls. Similar observations were made in EG/EGE mice. In Siglec-8–transgenic mice, anti–Siglec-8 mAb administration significantly reduced eosinophils and MCs in the stomach, small intestine, and mesenteric lymph nodes and decreased levels of inflammatory mediators. In summary, these findings suggest a role for both MCs and eosinophils in EGID pathogenesis and support the evaluation of anti–Siglec-8 as a therapeutic approach that targets both eosinophils and MCs.

Authors

Bradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Bruce S. Bochner, Henrik S. Rasmussen, Kathryn Peterson, Christopher Bebbington, Nenad Tomasevic

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Figure 1

EG and EoE patient tissues have significantly increased numbers of eosinophils and mast cells compared with nondiseased control tissue.

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EG and EoE patient tissues have significantly increased numbers of eosin...
(A) Flow cytometry gating strategy used to identify immune cells, including eosinophils and mast cells, in human stomach tissue from patients with EG. Percentage of (B) eosinophils (CD45+7AAD–SSChiCD16–CD24+) and (C) mast cells (CD45+7AAD–SSChiCD16–CD24–) present in nondiseased (black) or EG (gray) stomach tissue identified using the gating strategy in A. (D) Percentage of neutrophils, T cells, monocytes, DCs, and other (B cells, NK cells, macrophages, basophils) in nondiseased (black) or EG (gray) stomach tissue using the gating strategy shown in A. Percentage of (E) eosinophils and (F) mast cells present in nondiseased (black) or EoE (gray) esophageal tissue identified using the gating strategy in A. The percentage of cells was derived from the CD45+ viable population. Data are plotted as mean ± SEM for n = 7 nondiseased stomach tissue and n = 4 nondiseased esophageal tissue; n = 4 EG, n = 3 EG + EoE, and n = 3 EoE patients. *P < 0.05; **P < 0.01 by Mann-Whitney U test.

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