Department of Dermatology and Venereology, Innsbruck Medical University, A-6020 Innsbruck, Austria.
J Immunother. 2010 Feb-Mar;33(2):115-25. doi: 10.1097/CJI.0b013e3181b8ef5f.
The efficiency of immunotherapy using tumor-antigen-loaded dendritic cells (DCs) is severely limited by the impaired migration of injected cells from the application site to the draining lymph nodes. As described earlier, pretreatment of the injection site with inflammatory cytokines enhances DC migration. We wanted to test whether toll-like receptor (TLR) ligands can improve migration of murine bone marrow-derived DC (BMDC) and the subsequent T-cell responses. For this purpose, we established an experimental setup closely resembling human vaccination protocols that served to investigate DC migration from the skin to the draining lymph nodes. We observed that BMDC, matured with a cytokine cocktail (tumor necrosis factor-alpha, interleukin-beta, interleukin-6, prostaglandin E2), strongly expressed CCR7. The migration efficiency of adoptively transferred mature BMDCs was determined by the number of cells injected and the application site. We decided to inject DC intradermally into the ear skin and investigated the effects of pretreatment of the injection site with various TLR ligands. Conditioning of the skin site with the TLR ligands CpG and Peptidoglycan increased the number of DCs arriving in the lymph node. Mechanical stress applied to the skin, such as tape stripping of the skin was equally effective. Importantly, only pretreatment with CpG enhanced responses of endogenous CD8 T cells. Thus, conditioning of the injection site with the TLR ligand CpG could be a new promising way to improve the outcome of DC immunotherapy.
肿瘤抗原负载树突状细胞（DC）的免疫疗法的效率受到注入细胞从施药部位向引流淋巴结迁移的受损的限制。如前所述，用炎性细胞因子预处理施药部位可增强 DC 的迁移。我们想测试 Toll 样受体（TLR）配体是否可以改善鼠骨髓来源的 DC（BMDC）的迁移以及随后的 T 细胞反应。为此，我们建立了一个实验设置，该设置非常类似于人类疫苗接种方案，用于研究 DC 从皮肤向引流淋巴结的迁移。我们观察到，用细胞因子鸡尾酒（肿瘤坏死因子-α、白细胞介素-β、白细胞介素-6、前列腺素 E2）成熟的 BMDC 强烈表达 CCR7。通过注入的细胞数量和应用部位来确定过继转移的成熟 BMDC 的迁移效率。我们决定将 DC 皮内注射到耳部皮肤，并研究用各种 TLR 配体预处理施药部位的效果。用 TLR 配体 CpG 和肽聚糖预处理皮肤部位可增加到达淋巴结的 DC 数量。对皮肤施加机械应力，如皮肤胶带剥离，同样有效。重要的是，只有 CpG 的预处理增强了内源性 CD8 T 细胞的反应。因此，用 TLR 配体 CpG 预处理注射部位可能是改善 DC 免疫疗法效果的一种新的有希望的方法。
