Canine Recombinant Adenovirus Vector Induces an Immunogenicity-Related Gene Expression Profile in Skin-Migrated CD11b+ -Type DCs

Gene expression profiling of the blood cell response induced early after vaccination has previously been demonstrated to predict the immunogenicity of vaccines. In this study, we evaluated whether the analysis of the gene expression profile of skin-migrated dendritic cells (DCs) could be informative for the in vitro prediction of immunogenicity of vaccine, using canine adenovirus serotype 2 (CAV2) as vaccine vector. CAV2 has been shown to induce immunity to transgenes in several species including sheep and is an interesting alternative to human adenovirus-based vectors, based on the safety records of the parental strain in dogs and the lack of pre-existing immunity in non-host species. Skin-migrated DCs were collected from pseudo-afferent lymph in sheep. Both the CD11b+ -type and CD103+ -type skin-migrated DCs were transduced by CAV2. An analysis of the global gene response to CAV2 in the two skin DC subsets showed that the gene response in CD11b+ -type DCs was far higher and broader than in the CD103+ -type DCs. A newly released integrative analytic tool from Ingenuity systems revealed that the CAV2-modulated genes in the CD11b+ -type DCs clustered in several activated immunogenicity-related functions, such as immune response, immune cell trafficking and inflammation. Thus gene profiling in skin-migrated DC in vitro indicates that the CD11b+ DC type is more responsive to CAV2 than the CD103+ DC type, and provides valuable information to help in evaluating and possibly improving viral vector vaccine effectiveness.

此前已有研究证实，疫苗接种后早期诱导的血细胞应答基因表达谱，可用于预测疫苗的免疫原性。本研究以2型犬腺病毒（canine adenovirus serotype 2, CAV2）为疫苗载体，旨在探究皮肤迁移树突状细胞（dendritic cells, DCs）的基因表达谱分析能否为疫苗免疫原性的体外预测提供有效信息。已有研究表明，CAV2可在包括绵羊在内的多个物种中诱导外源基因免疫；基于其亲本毒株在犬体内的安全使用记录，以及非宿主物种中不存在预存免疫的特性，CAV2是替代人腺病毒载体的极具潜力的候选方案。研究人员从绵羊的假性输入淋巴管中分离得到皮肤迁移DCs。CD11b+型与CD103+型皮肤迁移DCs均可被CAV2转导。对两种皮肤DC亚群的CAV2应答全基因谱进行分析后发现，CD11b+型DCs的基因应答强度与覆盖范围均远高于CD103+型DCs。Ingenuity系统（Ingenuity Systems）新发布的整合分析工具显示，CD11b+型DCs中受CAV2调控的基因，聚类富集于多个与免疫原性相关的激活性功能模块，包括免疫应答、免疫细胞趋化与炎症反应。综上，体外皮肤迁移DCs的基因谱分析表明，CD11b+型DCs对CAV2的应答活性显著强于CD103+型DCs，该结果可为评估乃至优化病毒载体疫苗的效力提供极具价值的参考依据。