Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions

Takumi Kiwamoto, Norihito Kawasaki, James C. Paulson, Bruce S. Bochner

Research output: Contribution to journalArticle

Abstract

Siglecs (sialic acid immunoglobulin-like lectins) are members of the immunoglobulin gene family that contain sialoside binding N-terminal domains. They are cell surface proteins found predominantly on cells of the immune system. Among them, Siglec-8 is uniquely expressed by human eosinophils and mast cells, as well as basophils. Engaging this structure with antibodies or glycan ligands results in apoptosis in human eosinophils and inhibition of release of preformed and newly generated mediators from human mast cells without affecting their survival. Pro-apoptotic effects are also seen when its closest functional paralog, Siglec-F, on mouse eosinophils is similarly engaged in vitro, and beneficial effects are observed after administration of Siglec-F antibody using models of eosinophilic pulmonary and gastrointestinal inflammation in vivo. Siglec-8 targeting may thus provide a means to specifically inhibit or deplete these cell types. Cell-directed therapies are increasingly sought after by the pharmaceutical industry for their potential to reduce side effects and increase safety. The challenge is to identify suitable targets on the cell type of interest, and selectively deliver a therapeutic agent. By targeting Siglec-8, monoclonal antibodies and glycan ligand-conjugated nanoparticles may be ideally suited for treatment of eosinophil and mast cell-related diseases, such as asthma, chronic rhinosinusitis, chronic urticaria, hypereosinophilic syndromes, mast cell and eosinophil malignancies and eosinophilic gastrointestinal disorders.

Original languageEnglish (US)
Pages (from-to)327-336
Number of pages10
JournalPharmacology and Therapeutics
Volume135
Issue number3
DOIs
StatePublished - Sep 2012

Fingerprint

Sialic Acid Binding Immunoglobulin-like Lectins
Eosinophils
Mast Cells
Polysaccharides
Hypereosinophilic Syndrome
Mastocytosis
Ligands
Immunoglobulin Genes
Basophils
Antibodies
Urticaria
Drug Industry
N-Acetylneuraminic Acid
Cell- and Tissue-Based Therapy
Lectins
Nanoparticles
Immunoglobulins
Immune System
Pneumonia
Membrane Proteins

Keywords

  • Allergic diseases
  • Apoptosis
  • Glycan ligands
  • Liposomes
  • Siglec-8
  • Siglec-F

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. / Kiwamoto, Takumi; Kawasaki, Norihito; Paulson, James C.; Bochner, Bruce S.

In: Pharmacology and Therapeutics, Vol. 135, No. 3, 09.2012, p. 327-336.

Research output: Contribution to journalArticle

Kiwamoto, Takumi ; Kawasaki, Norihito ; Paulson, James C. ; Bochner, Bruce S. / Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. In: Pharmacology and Therapeutics. 2012 ; Vol. 135, No. 3. pp. 327-336.
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