POTENT INHIBITION OF CTLA-4 EXPRESSION BY AN ANTI-CTLA-4 RIBOZYME

Blockading the negative-regulatory CTLA-4 receptor has emerged as a po werful strategy with clinical potential to enhance T-cell responses. S ome experimental tumors, for example, are rejected when anti-CTLA-4 an tibodies are administered in vivo. The concise target cells and downst ream events, however, remain to be defined. The development of gene tr ansfer reagents that inhibit CTLA-4 may facilitate such investigations and may expand the therapeutic range. This communication describes an anti-CTLA-4 hairpin ribozyme that specifically abrogates CTLA-4 expre ssion after gene transfer into a murine T-cell model. The analysis of multiple and independently derived clones and bulk cultures showed tha t CTLA-4 induction was inhibited >90% at the RNA level and that it was undetectable at the protein level, with and without selective pressur e. This potent inhibition required the catalytic function of the riboz yme. The anti-CTLA-4 ribozyme may be an alternative tool with which to continue the functional and therapeutical exploration of CTLA-4. (C) 1998 Academic Press.