Potent inhibition of CTLA-4 expression by an anti-CTLA-4 ribozyme.
Blockading the negative-regulatory CTLA-4 receptor has emerged as a powerful strategy with clinical potential to enhance T-cell responses. Some experimental tumors, for example, are rejected when anti-CTLA-4 antibodies are administered in vivo. The concise target cells and downstream events, however, remain to be defined. The development of gene transfer 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 expression after gene transfer into a murine T-cell model. The analysis of multiple and independently derived clones and bulk cultures showed that CTLA-4 induction was inhibited > 90% at the RNA level and that it was undetectable at the protein level, with and without selective pressure. This potent inhibition required the catalytic function of the ribozyme. The anti-CTLA-4 ribozyme may be an alternative tool with which to continue the functional and therapeutical exploration of CTLA-4.
Cepero
E
E
Department of Microbiology and Immunology, University of Miami, School of Medicine, Florida 33101, USA.
Hnatyszyn
H J
HJ
Kraus
G
G
Lichtenheld
M G
MG
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D002999:Clone Cells / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D018014:Gene Transfer Techniques; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000235:genetics; D051379:Mice; D016337:RNA, Catalytic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014162:Transfection / Q000235:genetics
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D016337:RNA, Catalytic; D012333:RNA, Messenger; D000069594:Abatacept