Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
Blood. 2011 Dec 22;118(26):6836-44. doi: 10.1182/blood-2011-07-367615. Epub 2011 Oct 3.
Effective vaccines consist of 2 components: immunodominant antigens and effective adjuvants. Whereas it has been demonstrated that targeted delivery of antigens to dendritic cells (DCs) improves vaccine efficacy, we report here that co-targeting of TLR ligands (TLRLs) to DCs strongly enhances adjuvanticity and immunity. We encapsulated ligands for intracellular TLRs within biodegradable nanoparticles coated with Abs recognizing DC-specific receptors. Targeted delivery of TLRLs to human DCs enhanced the maturation and production of immune stimulatory cytokines and the Ag-specific activation of naive CD8(+) T cells. In vivo studies demonstrated that nanoparticles carrying Ag induced cytotoxic T-lymphocyte responses at 100-fold lower adjuvant dose when TLRLs were co-encapsulated instead of administered in soluble form. Moreover, the efficacy of these targeted TLRLs reduced the serum cytokine storm and related toxicity that is associated with administration of soluble TLRLs. We conclude that the targeted delivery of adjuvants may improve the efficacy and safety of DC-based vaccines.
有效疫苗包含 2 种成分：免疫显性抗原和有效的佐剂。虽然已经证实将抗原靶向递送至树突状细胞（DC）可提高疫苗效力，但我们在此报告，TLR 配体（TLRL）靶向递送至 DC 可显著增强佐剂作用和免疫原性。我们将细胞内 TLR 的配体包封在被识别 DC 特异性受体的 Ab 包被的可生物降解纳米颗粒内。TLRL 靶向递送至人 DC 可增强成熟和免疫刺激性细胞因子的产生，以及 Ag 特异性初始 CD8(+)T 细胞的激活。体内研究表明，当将 TLRL 共同包封于纳米颗粒而非以可溶性形式给药时，携带 Ag 的纳米颗粒以 100 倍更低的佐剂剂量诱导细胞毒性 T 淋巴细胞应答。此外，这些靶向 TLRL 的疗效降低了与可溶性 TLRL 给药相关的血清细胞因子风暴和相关毒性。我们得出结论，佐剂的靶向递送可提高基于 DC 的疫苗的效力和安全性。
