Prolonged maturation and enhanced transduction of dendritic cells migrated from human skin explants after in situ delivery of CD40-targeted adenoviral vectors
Prolonged maturation and enhanced transduction of dendritic cells migrated from human skin explants after in situ delivery of CD40-targeted adenoviral vectors
复制标题
DOI：
10.4049/jimmunol.169.9.5322
复制
发表时间：
2002-11-01
影响因子：
4.4
通讯作者：
Gerritsen, WR
中科院分区：
文献类型：
--
作者：
de Gruijl, TD;Luykx-de Bakker, SA;Gerritsen, WR
用携带肿瘤相关抗原遗传密码的病毒载体或裸DNA进行治疗性肿瘤疫苗接种，关键取决于树突状细胞（DC）的体内转导。主要是非专业的APC和只有少量的DC的转染可能会妨碍适当的T细胞活化。因此，本研究的目的是靶向的、选择性的和增强的DC原位转导。使用人皮肤外植体模型来探索在皮内注射双特异性Ab缀合物以将腺病毒（Ad）载体直接连接至DC表面上的CD40之后皮肤DC的靶向转导。因此实现了显著增强的转导效率和选择性，以及增加的迁移DC的活化状态。此外，由CD40靶向的Ad转导的DC在迁移开始后维持其Ag特异性CTL刺激能力长达1周，而由非靶向的Ad转导的DC在那时已经失去了这种能力。由于体内靶向DC可能不需要体外培养自体DC用于过继转移，因此CD40靶向的Ad载体构成了用于肿瘤免疫治疗的有希望的新疫苗模式。
Therapeutic tumor vaccination with viral vectors or naked DNA, carrying the genetic code for tumor-associated Ags, critically depends on the in vivo transduction of dendritic cells (DC). Transfection of predominantly nonprofessional APC and only small numbers of DC may hamper proper T cell activation. Aim of this study was, therefore, the targeted, selective, and enhanced in situ transduction of DC. A human skin explant model was used to explore targeted transduction of cutaneous DC after intradermal injection of a bispecific Ab conjugate to link adenoviral (Ad) vectors directly to CD40 on the DC surface. A significantly enhanced transduction efficiency and selectivity, and an increased activation state of migrating DC were thus achieved. Moreover, DC transduced by CD40-targeted Ad maintained their Ag-specific CTL-stimulatory ability for up to 1 wk after the start of migration, in contrast to DC transduced by untargeted Ad, which had lost this capacity by that time. Because DC targeting in vivo might obviate the need for the in vitro culture of autologous DC for adoptive transfer, CD40-targeted Ad vectors constitute a promising new vaccine modality for tumor immunotherapy.