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https://hdl.handle.net/2440/8678
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Type: | Journal article |
Title: | Simultaneous antagonism of interleukin-5, granulocyte-macrophage colony-stimulting factor, and interleukin-3 stimulation of human eosinophils by targetting the common cytokine binding site of their receptors |
Author: | Sun, Q. Jones, K. McClure, B. Cambareri, B. Zacharakis, B. Iversen, P. Stomski, F. Woodcock, J. Bagley, C. D'Andrea, R. Lopez, A. |
Citation: | Blood, 1999; 94(6):1943-1951 |
Publisher: | AMER SOC HEMATOLOGY |
Issue Date: | 1999 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Q. Sun, K. Jones, B. McClure, B. Cambareri, B. Zacharakis, P.O. Iversen, F. Stomski, J.M. Woodcock, C.J. Bagley, R. D’Andrea, and A.F. Lopez |
Abstract: | Human interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3 are eosinophilopoietic cytokines implicated in allergy in general and in the inflammation of the airways specifically as seen in asthma. All 3 cytokines function through cell surface receptors that comprise a ligand-specific alpha chain and a shared subunit (beta(c)). Although binding of IL-5, GM-CSF, and IL-3 to their respective receptor alpha chains is the first step in receptor activation, it is the recruitment of beta(c) that allows high-affinity binding and signal transduction to proceed. Thus, beta(c) is a valid yet untested target for antiasthma drugs with the added advantage of potentially allowing antagonism of all 3 eosinophil-acting cytokines with a single compound. We show here the first development of such an agent in the form of a monoclonal antibody (MoAb), BION-1, raised against the isolated membrane proximal domain of beta(c). BION-1 blocked eosinophil production, survival, and activation stimulated by IL-5 as well as by GM-CSF and IL-3. Studies of the mechanism of this antagonism showed that BION-1 prevented the high-affinity binding of (125)I-IL-5, (125)I-GM-CSF, and (125)I-IL-3 to purified human eosinophils and that it bound to the major cytokine binding site of beta(c). Interestingly, epitope analysis using several beta(c) mutants showed that BION-1 interacted with residues different from those used by IL-5, GM-CSF, and IL-3. Furthermore, coimmunoprecipitation experiments showed that BION-1 prevented ligand-induced receptor dimerization and phosphorylation of beta(c), suggesting that ligand contact with beta(c) is a prerequisite for recruitment of beta(c), receptor dimerization, and consequent activation. These results demonstrate the feasibility of simultaneously inhibiting IL-5, GM-CSF, and IL-3 function with a single agent and that BION-1 represents a new tool and lead compound with which to identify and generate further agents for the treatment of eosinophil-dependent diseases such as asthma. |
Keywords: | Leukocytes Eosinophils Neutrophils Monocytes CHO Cells Animals Humans Granulocyte-Macrophage Colony-Stimulating Factor Interleukin-3 Receptors, Granulocyte-Macrophage Colony-Stimulating Factor Receptors, Interleukin-3 Receptors, Interleukin Recombinant Proteins Interleukin-5 Transfection Lymphocyte Activation Cell Survival Binding Sites Kinetics Cricetinae Receptors, Interleukin-5 In Vitro Techniques |
Rights: | Copyright © 1999 The American Society of Hematology |
DOI: | 10.1182/blood.v94.6.1943.418k04_1943_1951 |
Published version: | http://dx.doi.org/10.1182/blood.v94.6.1943.418k04_1943_1951 |
Appears in Collections: | Aurora harvest Medicine publications |
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