Antisense modulation of interleukin-5 signal transduction

DETAILED DESCRIPTION OF THE INVENTION The present invention comprehends antisense compounds capable of modulating IL-5 signal transduction, preferably by modulating expression of IL-5 or IL-5 receptor.
alpha.
.
These compounds are useful for both research and therapeutic, including prophylactic, uses.
The human IL-5 receptor.
alpha.
gene contains 14 exons.
A membrane-anchored form of the receptor and two soluble forms have been identified.
The mRNA transcript encoding the membrane-anchored form of the human IL-5 receptor.
alpha.
contain exons 1-10 and 12-14.
Exon 11 is spliced out by an alternative splicing event.
The major soluble isoform (soluble form 1) is generated as a result of a normal splicing event and an in-frame stop codon in exon 11.
The other soluble form (soluble form 2) is generated by the absence of splicing and therefore is generated by reading into intron 11.
Tuypens et al.
Eur.
Cytokine Netw.
, 1992, 3, 451-459.
The mRNA encoding the membrane form of the mouse IL-5 receptor.
alpha.
contains 11 exons.
The transmembrane domain of the receptor is encoded in exon 9.
Two mRNAs encoding soluble (secreted) forms of the receptor result from differential splicing events.
The mRNA encoding soluble form 1 of the receptor is missing exon 9 (exon 8 is spliced to exon 10) and the mRNA encoding soluble form 2 is missing exons 9 and 10 (exon 8 is spliced to exon 11).
Imamura et al.
, DNA and Cell Biol.
, 1994, 13, 283-292.
In both mouse and humans, there are both soluble forms and a membrane-bound form of IL-5 receptor.
alpha.
.
In mouse, the soluble form is expressed, though experiments are usually done by addition of exogenous recombinant soluble receptor.
Recombinant murine soluble IL-5 receptor.
alpha.
binds IL-5, and does not inhibit proliferation of the IL-5-responsive Y16B cell line.
In vivo, recombinant soluble murine IL-5 receptor.
alpha.
suppresses antigen-induced airway eosinophilia.
In humans, recombinant human soluble IL-5 receptor.
alpha.
binds human IL-5 and inhibits its biological activity in vitro, i