Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 143, Issue 6, Pages 2227-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2018.10.066
Keywords
Siglec-8; eosinophil; mast cell; soluble receptor; inhibitory receptor; apoptosis; hypereosinophilic syndrome; eosinophilic gastrointestinal disease; mastocytosis; monoclonal antibody
Categories
Funding
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH)
- NIH [AI097073]
- American Partnership for Eosinophilic Diseases (APFED)
- Buckeye Foundation
- Allakos, Inc.
- [K08 1K08DK097721-01]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001130, ZIAAI000249] Funding Source: NIH RePORTER
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Background: Sialic acid-binding immunoglobulin-like lectin (Siglec) 8 is selectively expressed on eosinophils, mast cells, and basophils and, when engaged on eosinophils, can cause cell death. Objective: We sought to characterize surface and soluble Siglec-8 (sSiglec-8) levels in normal donors (NDs) and eosinophilic donors (EOs) and assess the efficacy of anti-Siglec-8 antibodies in inducing eosinophil cell death in vitro. Methods: Eosinophil expression of Siglec-8 was assessed by using flow cytometry and quantitative PCR. Serum sSiglec-8 levels were measured by means of ELISA. Induction of eosinophil death by IgG(4) (chimeric 2E2 IgG(4)) and afucosylated IgG(1) (chimeric 2E2 IgG(1) [c2E2 IgG(1)]) anti-Siglec-8 antibodies was evaluated in vitro by using flow cytometry and in vivo in humanized mice. Results: Siglec-8 was consistently expressed on eosinophils from NDs and EOs and did not correlate with absolute eosinophil count or disease activity. sSiglec-8 levels were measurable in sera from most donors unrelated to absolute eosinophil counts or Siglec-8 surface expression. c2E2 IgG(1) and chimeric 2E2 IgG(4) were equally effective at inducing cell death (Annexin-V positivity) of purified eosinophils from NDs and EOs after overnight IL-5 priming. In contrast, killing of purified eosinophils without IL-5 was only seen in EOs, and natural killer cell-mediated eosinophil killing was seen only with c2E2 IgG(1). Finally, treatment of humanized mice with anti-Siglec antibody led to robust depletion of IL-5-induced eosinophilia in vivo. Conclusions: Siglec-8 is highly expressed on blood eosinophils from EOs and NDs and represents a potential therapeutic target for eosinophilic disorders. Enhanced killing of eosinophils in the presence of IL-5 might lead to increased efficacy in patients with IL-5-driven eosinophilia.
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