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• W2922386720 abstract "Introduction: Mast cells and eosinophils are known for their roles in driving inflammation and allergic disease. Pathologic accumulation and over—activation of mast cells and eosinophils have been implicated in certain chronic inflammatory diseases in the gastrointestinal (GI) tract including eosinophilic esophagitis, gastritis, gastroenteritis, and colitis. Collectively termed eosinophilic gastrointestinal diseases (EGIDs), these medical conditions can lead to reduced quality of life due to debilitating symptoms including dysphagia, abdominal pain, nausea, vomiting and diarrhea. While the pathogenesis of EGIDs is primarly thought to be driven by eosinophils, there is increasing evidence for the involvement of mast cells. Siglec—8 is an inhibitory receptor selectively expressed on human eosinophils and mast cells, and therefore represents a novel target for the treatment of EGIDs. AK002 is a novel, humanized, non—fucosylated IgG1 monoclonal antibody to Siglec—8. The expression of Siglec—8 and the activity of AK002 has not been previously evaluated in EGID tissue. Methods: Single—cell suspensions were prepared by enzymatic digestion offresh biopsies from patients clinically diagnosed with EGID. Multi—color flow cytometry was perfomed to quantify eosinophils and mast cells and to evaluate the activation state of mast cells. The ex vivo activity of AK002 was evaluated against eosinophils and mast cells in dissociated EGID biopsies compared to an isotype control antibody. Results: Tissue eosinophils and mast cells could be identified and characterized using flow cytometry from fresh biopsy specimens. Patients with EGID had increased numbers of GI mast cells and eosinophils compared to control samples (Figure 1). Mast cells in EGID tissue also displayed increased expression of markers of activation (eg CD63). Furthermore, GI mast cells and eosinophils displayed high levels of expression of Siglec—8 (Figure 2). Lastly, AK002 demonstrated anti—eosinophilic and mast cell inhibitory activity in ex vivo dissociated EGID tissue biopsies.1225_A Figure 1. Increased tissue mast cells and eosinophils in patients with EGID compared to normal controls. Eosinophils and mast cells were identified and quantified by flow cytometry in esophageal tissue from patients with EGID (n=2) or normal control (n=4). In patients with EGID, increased numbers of both mast cells and eosinophils were seen compared to normal controls.1225_B Figure 2. Mast cells and eosinophils in the GI tract display robust and selective expression of Siglec—8. Eosinophils (red; CD45+ 7AAD— CD16— CD117— CD49d+) and mast cells (blue; CD45+ 7AAD— CD117+ IgER+) were identified by flow cytometry in esophageal tissue from a patient with EGID (left) or normal control (right).Conclusion: Activated eosinophils and mast cells, key effector cells in EGIDs, were found in increased numbers in biopsy samples from patients with EGIDs. The selective and high expression of Siglec—8 on eosinophils and mast cells, and the activity of AK002, represent a potential novel approach for the treatment of EGIDs." @default.
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• W2922386720 date "2018-10-01" @default.
• W2922386720 modified "2023-10-17" @default.
• W2922386720 title "Siglec—8, a Novel Selective Target for Eosinophilic Gastrointestinal Diseases (EGIDs) Found on Eosinophils and Mast Cells in Human Tissue" @default.
• W2922386720 doi "https://doi.org/10.14309/00000434-201810001-01225" @default.
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