The effect of combined IL10 siRNA and CpG ODN as pathogen-mimicking microparticles on Th1/Th2 cytokine balance in dendritic cells and protective immunity against B cell lymphoma.
The effect of combined IL10 siRNA and CpG ODN as pathogen-mimicking microparticles on Th1/Th2 cytokine balance in dendritic cells and protective immunity against B cell lymphoma.
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DOI：
10.1016/j.biomaterials.2014.03.039
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发表时间：
2014-07
期刊：
影响因子：
14
通讯作者：
Roy K
中科院分区：
文献类型：
--
作者：
Pradhan P;Qin H;Leleux JA;Gwak D;Sakamaki I;Kwak LW;Roy K
癌症免疫疗法的成功通常取决于由抗原呈递细胞（特别是树突状细胞（DC））驱动的辅助性T细胞1（Th 1）和辅助性T细胞2（Th 2）应答的关键平衡。Th 1驱动的细胞毒性T细胞（CTL）应答是消除肿瘤细胞的关键。已经确定的是，CpG寡核苷酸（ODN），一种广泛研究的Toll样受体9（TLR 9）激动剂，用于增强Th 1应答，也诱导高水平的抗炎、Th 2促进细胞因子IL 10，其可以抑制所产生的Th 1应答。基于生物材料的免疫调节策略可以在CpG递送期间减少IL 10产生同时维持IL 12水平，这可以进一步增强Th 1/Th 2细胞因子平衡并改善抗肿瘤免疫应答。在这里，我们报告说，双重交付IL 10沉默siRNA沿着与CpG ODN相同的DC使用病原体模拟微粒（PMP），显着提高其Th 1/Th 2细胞因子的比例，通过同时抑制CpG诱导的IL 10的生产。TLR 3激动剂poly（I：C）的共递送对IL 10水平仅具有微小的影响。此外，在预防性小鼠B细胞淋巴瘤模型中，CpG ODN和IL 10 siRNA的同时免疫治疗增强了独特型DNA疫苗的免疫保护，而poly（I：C）和CpG的共递送没有增强保护。这些结果表明，PMPs可用于精确地调节TLR配体介导的免疫刺激在DC中，通过共递送的干扰素沉默siRNA，从而增强抗肿瘤免疫。
Success of an immunotherapy for cancer often depends on the critical balance of T helper 1 (Th1) and T helper 2 (Th2) responses driven by antigen presenting cells, specifically dendritic cells (DCs). Th1-driven cytotoxic T cell (CTL) responses are key to eliminating tumor cells. It is well established that CpG oligonucleotides (ODN), a widely studied Toll-like receptor 9 (TLR9) agonist, used to enhance Th1 response, also induces high levels of the anti-inflammatory, Th2-promoting cytokine IL10, which could dampen the resulting Th1 response. Biomaterials-based immunomodulatory strategies that can reduce IL10 production while maintaining IL12 levels during CpG delivery could further enhance the Th1/Th2 cytokine balance and improve anti-tumor immune response. Here we report that dual-delivery of IL10-silencing siRNA along with CpG ODN to the same DCs using pathogen-mimicking microparticles (PMPs), significantly enhances their Th1/Th2 cytokine ratio through concurrent inhibition of CpG-induced IL10 production. Co-delivery of poly(I:C), a TLR3 agonist had only minor effects on IL10 levels. Further, simultaneous immunotherapy with CpG ODN and IL10 siRNA enhanced immune protection of an idiotype DNA vaccine in a prophylactic murine model of B cell lymphoma whereas co-delivery of poly(I:C) and CpG did not enhance protection. These results suggest that PMPs can be used to precisely modulate TLR ligand-mediated immune-stimulation in DCs, through co-delivery of cytokine-silencing siRNAs and thereby boost antitumor immunity.