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经鼻给予的原代树突状细胞疫苗的体内转运和免疫刺激潜力。

In vivo trafficking and immunostimulatory potential of an intranasally-administered primary dendritic cell-based vaccine.

机构信息

Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, OK 73117, USA.

出版信息

BMC Immunol. 2010 Dec 10;11:60. doi: 10.1186/1471-2172-11-60.

DOI:10.1186/1471-2172-11-60
PMID:21143974
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3018378/
Abstract

BACKGROUND

Coccidioidomycosis or Valley fever is caused by a highly virulent fungal pathogen: Coccidioides posadasii or immitis. Vaccine development against Coccidioides is of contemporary interest because a large number of relapses and clinical failures are reported with antifungal agents. An efficient Th1 response engenders protection. Thus, we have focused on developing a dendritic cell (DC)-based vaccine for coccidioidomycosis. In this study, we investigated the immunostimulatory characteristics of an intranasal primary DC-vaccine in BALB/c mouse strain that is most susceptible to coccidioidomycosis. The DCs were transfected nonvirally with Coccidioides-Ag2/PRA-cDNA. Expression of DC-markers, Ag2/PRA and cytokines were studied by flow cytometry, dot-immunoblotting and cytometric bead array methods, respectively. The T cell activation was studied by assessing the upregulation of activation markers in a DC-T cell co-culture assay. For trafficking, the DCs were co-transfected with a plasmid DNA encoding HSV1 thymidine kinase (TK) and administered intranasally into syngeneic mice. The trafficking and homing of TK-expressing DCs were monitored with positron emission tomography (PET) using 18F-FIAU probe. Based on the PET-probe accumulation in vaccinated mice, selected tissues were studied for antigen-specific response and T cell phenotypes using ELISPOT and flow cytometry, respectively.

RESULTS

We found that the primary DCs transfected with Coccidioides-Ag2/PRA-cDNA were of immature immunophenotype, expressed Ag2/PRA and activated naïve T cells. In PET images and subsequent biodistribution, intranasally-administered DCs were found to migrate in blood, lung and thymus; lymphocytes showed generation of T effector memory cell population (T(EM)) and IFN-γ release.

CONCLUSIONS

In conclusion, our results demonstrate that the intranasally-administered primary DC vaccine is capable of inducing Ag2/PRA-specific T cell response. Unique approaches utilized in our study represent an attractive and novel means of producing and evaluating an autologous DC-based vaccine.

摘要

背景

球孢子菌病或山谷热是由一种高毒力的真菌病原体引起的：荚膜组织胞浆菌或 immitis。针对球孢子菌的疫苗开发具有当代意义，因为报道了大量抗真菌药物治疗失败和复发的病例。有效的 Th1 反应会产生保护作用。因此，我们专注于开发针对球孢子菌病的树突状细胞 (DC) 疫苗。在这项研究中，我们研究了 BALB/c 小鼠品系中鼻腔内初级 DC 疫苗的免疫刺激特性，该品系最易感染球孢子菌病。DC 未经病毒转染转染有 Coccidioides-Ag2/PRA-cDNA。通过流式细胞术、斑点免疫印迹和细胞因子流式微球阵列方法分别研究 DC 标志物、Ag2/PRA 和细胞因子的表达。通过评估 DC-T 细胞共培养试验中激活标志物的上调来研究 T 细胞的激活。为了进行运输，将 DC 与编码 HSV1 胸苷激酶 (TK) 的质粒 DNA 共转染，并通过鼻腔内给药进入同基因小鼠。使用 18F-FIAU 探针通过正电子发射断层扫描 (PET) 监测 TK 表达的 DC 的运输和归巢。基于接种疫苗小鼠中 PET 探针的积累，使用 ELISPOT 和流式细胞术分别研究了选定组织中的抗原特异性反应和 T 细胞表型。

结果

我们发现，用 Coccidioides-Ag2/PRA-cDNA 转染的初级 DC 具有不成熟的免疫表型，表达 Ag2/PRA 并激活幼稚 T 细胞。在 PET 图像和随后的生物分布中，发现鼻腔内给予的 DC 迁移到血液、肺和胸腺中；淋巴细胞显示产生 T 效应记忆细胞群（T(EM)）和 IFN-γ 释放。

结论

总之，我们的结果表明，鼻腔内给予的初级 DC 疫苗能够诱导 Ag2/PRA 特异性 T 细胞反应。我们研究中使用的独特方法代表了生产和评估自体 DC 疫苗的一种有吸引力和新颖的手段。

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