In vitro and in vivo inhibition of interleukin (IL)-5 - Mediated eosinopoiesis by murine IL-5R alpha antisense oligonucleotide

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