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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 2, February, 2001 116-122

In Vitro and In Vivo Inhibition of Interleukin (IL)-5-Mediated Eosinopoiesis by Murine IL-5Ralpha Antisense Oligonucleotide

Estelle Lach-Trifilieff, Robert A. McKay, Brett P. Monia, James G. Karras, and Christoph Walker

Novartis Horsham Research Centre, Horsham, United Kingdom; and Department of Molecular & Cellular Pharmacology, ISIS Pharmaceuticals, Carlsbad, California

The unique role of interleukin (IL)-5 in eosinophil production, activation, and localization makes this cytokine a prime target for therapeutic intervention in diseases characterized by a selective blood and tissue eosinophilia. In an attempt to block the effects of IL-5 on eosinophils, a strategy was developed to suppress the expression of the IL-5 receptor alpha  chain (IL-5Ralpha ) by antisense oligonucleotides (ASOs). IL-5Ralpha ASOs were identified which selectively and specifically suppress the expression of messenger RNA and proteins of both the membrane and the soluble form of the receptor in constitutively IL-5R-expressing murine BCL-1 cells in vitro. Moreover, these IL-5Ralpha -specific ASOs were able to selectively inhibit the IL-5-induced eosinopoesis from murine fetal liver and bone marrow cells in vitro, suggesting that these molecules may affect the development of IL-5-mediated eosinophilia in vivo. Indeed, intravenous administration of IL-5Ralpha -specific ASOs not only suppressed the bone-marrow and blood eosinophilia in mice after short-term treatment with recombinant murine IL-5 but also inhibited the development of blood and tissue eosinophilia in a ragweed-induced allergic peritonitis model. Thus, blocking the expression of IL-5Ralpha on eosinophil using ASOs may have therapeutic benefits in eosinophilic diseases such as asthma.




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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2001 American Thoracic Society. 		  CCM abstracts