Cepero E, Hnatyszyn H J, Kraus G, Lichtenheld M G
Department of Microbiology and Immunology, University of Miami, School of Medicine, Florida 33101, USA.
Biochem Biophys Res Commun. 1998 Jun 29;247(3):838-43. doi: 10.1006/bbrc.1998.8889.
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.
阻断负调节性细胞毒性T淋巴细胞相关抗原4（CTLA-4）受体已成为一种具有增强T细胞反应临床潜力的强大策略。例如，在体内施用抗CTLA-4抗体时，一些实验性肿瘤会被排斥。然而，确切的靶细胞和下游事件仍有待确定。抑制CTLA-4的基因转移试剂的开发可能有助于此类研究，并可能扩大治疗范围。本通讯描述了一种抗CTLA-4发夹状核酶，其在基因转移到小鼠T细胞模型后可特异性消除CTLA-4表达。对多个独立衍生的克隆和大量培养物的分析表明，无论有无选择压力，CTLA-4的诱导在RNA水平上被抑制>90%，在蛋白质水平上无法检测到。这种强效抑制需要核酶的催化功能。抗CTLA-4核酶可能是继续对CTLA-4进行功能和治疗探索的另一种工具。
