Reviews and feature articleNovel targeted therapies for eosinophilic disorders
Section snippets
Eosinophil ontogeny
As is true of all hematopoietic cells, eosinophils differentiate from CD34+ multipotential myeloid progenitors in the bone marrow. These myeloid progenitors give rise to CD34+ cells that also express GATA-1 and IL-5 receptor (IL-5R) α.3, 4 The CD34+IL-5Rα+ eosinophil-committed progenitors undergo further development in response to IL-3, GM-CSF, and IL-5, the most lineage-specific of the cytokines involved in eosinophil hematopoiesis.3, 5 It is because of this lineage specificity that therapies
IL-5–related targets
Targeting IL-5 (or IL-5R) is an appealing approach to the treatment of patients with all types of HESs, given the specificity of this cytokine for the eosinophil lineage and the assumption that tissue damage in patients with HESs is directly related to the presence of activated eosinophils. Anti–IL-5 antibodies target eosinophils by binding to IL-5, interfering with its ligation to IL-5Rα expressed on the eosinophil membrane. Two different humanized anti–IL-5 antibodies, mepolizumab and
Eosinophil survival
There are numerous preclinical pathways that are currently being pursued for the treatment of eosinophil-associated diseases. Interfering with eosinophil-inhibitory receptors involves direct engagement of inhibitory receptors with activating ligands (including antibodies) that result in impairment of eosinophil functional responses or survival signals or directly induce apoptosis. For example, anti–Siglec-8 (or anti–Siglec-F in the mouse) has the capacity to induce direct eosinophil apoptosis
Summary and future directions
Eosinophilic disorders are chronic conditions that require long-term treatment for the prevention of clinical manifestations. Morbidity and mortality for many eosinophilic disorders remain high, and current treatment options are limited by lack of efficacy, significant toxicity, or both. Recent advances in our understanding of eosinophil biology have paved the way for the development of several promising novel therapies. Although clinical trial development in these therapeutic areas has been
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Appendix A. CD molecules
Lipid, peptide and cytokine mediators elaborated by eosinophils
Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells
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Differential secretion of cytokines
Sci STKE
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Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD
Supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH), and by the Office of Rare Diseases/NIH.
Disclosure of potential conflict of interest: M. E. Wechsler has received research support from the National Institutes of Health (NIH); has received consulting fees from GlaxoSmithKline, Cephalon, Novartis, Sepracor/Sunovion, Schering-Plough, NKT Therapeutics, Asthmatx/BSCI, Genzyme, MapPharma, Genentech, and Boehringer Ingelheim; and has received honoraria from Merck. B. S. Bochner has received grants from the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute; has consultant arrangements with Sanofi-Aventis, Genentech, Merck, Roche, GlaxoSmithKline, TEVA, GlycoFi, and Medicis; is on a scientific advisory board for Merck; is a coinventor on existing and pending Siglec-8–related patents; might be entitled to a share of royalties received by his university on the potential sales of Siglec-8–related products but thus far has received no such royalties; receives royalties from UpToDate and Elsevier; is a cofounder of and has purchased stock in Allakos; and holds stock options for Glycomimetics. G. M. Gauvreau has received research support from Topigen Pharma. G. J. Gleich is a board member of the American Partnership for Eosinophilic Disorders (APFED) without compensation; has received consultancy fees from GlaxoSmithKline; has received research support from TRIA Bioscience Corp and ImmViz; has a patent with ImmViz; has received royalties from Teva; and has stock/stock options in Immune Design Corp. T. Henkel has received consultancy fees from Cephalon and is employed by and has received stock/stock options in Ception Therapeutics. R. Kolbeck is employed by and owns stock/stock options in MedImmune. S. K. Mathur has received consultancy fees from Teva Pharmaceuticals, is employed by the University of Wisconsin and William S Middleton VA Hospital, and has received research support from the NIH. H. Ortega is employed by and has received stock/stock options in GlaxoSmithKline. P. Renzi has received research support, consulting fees, and fees for participation in review activities from Pharmaxis and has received royalties and owns a patent as the inventor of TPI-ASM8. M. E. Rothenberg is a member of the board for APFED and the International Eosinophil Society, has received consultancy fees from Immune Pharmaceuticals, is the inventor of patents owned by Cincinnati Children's, and has stock/stock options in Immune Pharmaceuticals and Teva. F. Roufosse has received consulting fees and travel support from GlaxoSmithKline and received royalties from UpToDate Online. D. Simon has provided expert testimony for Basilea Pharmaceutica and Astellas Schweiz, has received research support from OPO Foundation Zurich, and has received lecture fees from Basilea Pharmaceutica. H.-U. Simon has received consultancy fees from Pfizer. P. F. Weller has received consultancy fees from GlaxoSmithKline and receives royalties from UpToDate. A. Wardlaw was a member of the Cephalon-Teva data monitoring board; has received research support from Pfizer and GlaxoSmithKline; and has provided legal consultation/expert witness testimony for Bayer. The rest of the authors declare that they have no relevant conflicts of interest.