Targeting CpG oligonucleotides to the lymph node by nanoparticles elicits efficient antitumoral immunity
Targeting CpG oligonucleotides to the lymph node by nanoparticles elicits efficient antitumoral immunity
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DOI：
10.4049/jimmunol.181.5.2990
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发表时间：
2008-09-01
影响因子：
4.4
通讯作者：
Endres, Stefan
中科院分区：
文献类型：
--
作者：
Bourquin, Carole;Anz, David;Endres, Stefan
病毒核酸被Toll样受体家族和RIG - I样受体家族的特定模式识别受体所识别。合成的DNA和RNA寡核苷酸可通过这些受体激活免疫系统，并增强对抗原的抗体和CD8细胞毒性反应。然而，免疫刺激寡核苷酸的全身性应用也会导致免疫系统的全身性、非抗原特异性刺激。在这项研究中，我们将抗原特异性反应的诱导与通常与免疫刺激寡核苷酸相关的全身性免疫激活分离开来。通过阳离子化明胶基纳米颗粒递送结合TLR9的CpG寡脱氧核苷酸，可增强体内抗原特异性细胞毒性T细胞和抗体反应的产生。此外，用载有CpG的纳米颗粒免疫可在黑色素瘤小鼠模型中诱导保护性抗肿瘤反应。然而，与游离CpG相关的促炎细胞因子的全身性释放和广泛的免疫刺激完全被消除。此外，我们表明明胶纳米颗粒制剂可防止由CpG介导的淋巴滤泡的破坏。与游离CpG相反，纳米颗粒递送的CpG被选择性地靶向淋巴结中的抗原提呈细胞，在那里它们介导局部免疫刺激。我们描述了一种将免疫刺激寡核苷酸靶向免疫反应起始部位的新策略，同时防止免疫系统的无差别和全身性激活。
Viral nucleic acids are recognized by specific pattern-recognition receptors of the Toll-like and RIG-I-like receptor families. Synthetic DNA and RNA oligonucleotides can activate the immune system through these receptors and potentiate Ab and CD8 cytotoxic responses to Ags. Systemic application of immunostimulatory oligonucleotides however also results in a generalized, non-Ag-specific stimulation of the immune system. In this study, we have dissociated the induction of an Ag-specific response from the systemic immune activation generally associated with immunostimulatory oligonucleotides. Delivery of CpG oligodeoxynucleotidesr that bind TLR9 by cationized gelatin-based nanoparticles potentiates the in vivo generation of an Ag-specific cytotoxic T cell and Ab response. Furthermore, immunization with CpG-loaded nanoparticles induces a protective antitumoral response in a murine model of melanoma. The systemic release of proinflammatory cytokines and widespread immunostimulation associated with free CpG is however completely abolished. In addition, we show that gelatin nanoparticle formulation prevents the destruction of lymphoid follicles mediated by CpG. Nanoparticle-delivered CpG, in contrast to free CpG, are selectively targeted to APCs in the lymph nodes where they mediate local immune stimulation. We describe a novel strategy to target immunostimulatory oligonucleotides to the initiation site of the immune response while at the same time protecting from an indiscriminate and generalized activation of the immune system.