Tillman B W, de Gruijl T D, Luykx-de Bakker S A, Scheper R J, Pinedo H M, Curiel T J, Gerritsen W R, Curiel D T
Gene Therapy Program, University of Alabama, Birmingham 35294, USA.
J Immunol. 1999 Jun 1;162(11):6378-83.
Important therapeutic applications of genetically modified dendritic cells (DC) have been proposed; however, current vector systems have demonstrated only limited gene delivery efficacy to this cell type. By means of bispecific Abs, we have dramatically enhanced gene transfer to monocyte derived DC (MDDC) by retargeting adenoviral (Ad) vectors to a marker expressed on DC, CD40. Adenovirus targeted to CD40 demonstrated dramatic improvements in gene transfer relative to untargeted Ad vectors. Fundamental to the novelty of this system is the capacity of the vector itself to modulate the immunological status of the MDDC. This vector induces DC maturation as demonstrated phenotypically by increased expression of CD83, MHC, and costimulatory molecules, as well as functionally by production of IL-12 and an enhanced allostimulatory capacity in a MLR. In comparing this vector to other Ad-based gene transfer systems, we have illustrated that the features of DC maturation are not a function of the Ad particle, but rather a consequence of targeting to the CD40 marker. This vector approach may thus mediate not only high-efficiency gene delivery but also serve a proactive role in DC activation that could ultimately strengthen the utility of this vector for immunotherapy strategies.
已经提出了基因改造树突状细胞（DC）的重要治疗应用；然而，目前的载体系统对这种细胞类型的基因递送效率仅显示出有限的效果。通过双特异性抗体，我们通过将腺病毒（Ad）载体重新靶向DC上表达的标志物CD40，显著增强了对单核细胞衍生DC（MDDC）的基因转移。与未靶向的Ad载体相比，靶向CD40的腺病毒在基因转移方面表现出显著改善。该系统新颖性的关键在于载体本身调节MDDC免疫状态的能力。这种载体诱导DC成熟，从表型上看，CD83、MHC和共刺激分子的表达增加，从功能上看，通过产生IL-12以及在混合淋巴细胞反应（MLR）中增强的同种异体刺激能力得以证明。在将这种载体与其他基于Ad的基因转移系统进行比较时，我们已经表明，DC成熟的特征不是Ad颗粒的作用，而是靶向CD40标志物的结果。因此，这种载体方法不仅可以介导高效的基因递送，还可以在DC激活中发挥积极作用，最终可能增强这种载体在免疫治疗策略中的效用。
