Nonlytic Fc-fused IL-7 synergizes with Mtb32 DNA vaccine to enhance antigen-specific T cell responses in a therapeutic model of tuberculosis
Nonlytic Fc-fused IL-7 synergizes with Mtb32 DNA vaccine to enhance antigen-specific T cell responses in a therapeutic model of tuberculosis
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DOI：
10.1016/j.vaccine.2013.04.029
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发表时间：
2013-06-12
期刊：
影响因子：
5.5
通讯作者：
Sung, Young-Chul
中科院分区：
文献类型：
--
作者：
Ahn, So-Shin;Jeon, Bo-Young;Sung, Young-Chul
在结核分枝杆菌 (MTB) 感染小鼠模型中评估了 DNA 疫苗免疫原性的改善，该模型检查了非裂解性 Fc 融合的 IL-7 DNA (IL-7-nFc) 和 Flt3 配体融合的 Mtb32 (F-Mtb32) DNA 的联合效应。小鼠气溶胶感染 MTB 后 4 周开始接受常规化疗 6 周。化疗开始后，进行五次 DNA 免疫，间隔两周。化疗期间同时给予 IL-7-nFc 和 F-Mtb32 DNA 可协同增强 Mtb32 特异性 T 细胞反应的强度，并通过 IFN-gamma ELISPOT 测定评估，在最后一次免疫后持续一年。地塞米松治疗后，与单独使用 F-MTb32 DNA 或对照小鼠相比，接受 IL-7-nFc 和 F-Mtb32 DNA 的小鼠中观察到 MTB 再激活显着降低。此外，与F-Mtb32 DNA或注射盐水的小鼠相比，用IL-7-nFc和F-Mtb32 DNA一起治疗的小鼠显示出改善的肺部病理学和降低的肺部炎症值。细胞内细胞因子染色显示，IL-7-nFc和F-Mtb32 DNA联合治疗诱导的保护水平与肺和脾中CTL表位肽刺激的Mtb32特异性IFN-γ分泌CD4(+)T细胞反应和CD8(+)T细胞反应增强有关。这些数据表明，IL-7-nFc 作为一种新型结核佐剂，可以通过显着增强共递送 DNA 疫苗诱导的 T 细胞免疫，促进治疗性结核 DNA 疫苗进入临床。 (C) 2013 Elsevier Ltd. 保留所有权利。
Improvement to the immunogenicity of DNA vaccines was evaluated in a Mycobacterium tuberculosis (MTB) infection mouse model examining the combined effects of nonlytic Fc-fused IL-7 DNA (IL-7-nFc) and Flt3-ligand fused Mtb32 (F-Mtb32) DNA. Mice were treated with conventional chemotherapy for 6 weeks from 4 weeks after aerosol infection of MTB. Following the start of chemotherapy, DNA immunizations were administered five times with 2-week intervals. Coadministration of IL-7-nFc and F-Mtb32 DNA given during chemotherapy synergistically enhanced the magnitude of Mtb32-specific T cell responses and sustained for one-year after the last immunization assessed by IFN-gamma ELISPOT assay. After dexamethasone treatment, a significantly reduced MTB reactivation was observed in mice received both IL-7-nFc and F-Mtb32 DNA, compared with F-MTb32 DNA alone or with control mice. In addition, mice treated with IL-7-nFc and F-Mtb32 DNA together showed improved lung pathology and reduced pulmonary inflammation values relative to F-Mtb32 DNA or saline injected mice. Intracellular cytokine staining revealed that the protection levels induced by combination therapy with IL-7-nFc and F-Mtb32 DNA was associated with enhanced Mtb32-specific IFN-gamma secreting CD4(+) T cell responses and CD8(+) T cell responses stimulated with CTL epitope peptide in the lungs and spleens. These data suggest that IL-7-nFc as a novel TB adjuvant may facilitate therapeutic TB DNA vaccine to the clinics through significant enhancement of codelivered DNA vaccine-induced T cell immunity. (C) 2013 Elsevier Ltd. All rights reserved.