The Nasal Dendritic Cell-Targeting Flt3 Ligand as a Safe Adjuvant Elicits Effective Protection against Fatal Pneumococcal Pneumonia
The Nasal Dendritic Cell-Targeting Flt3 Ligand as a Safe Adjuvant Elicits Effective Protection against Fatal Pneumococcal Pneumonia
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DOI：
10.1128/iai.01360-10
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发表时间：
2011-07-01
影响因子：
3.1
通讯作者：
Oishi, Kazunori
中科院分区：
文献类型：
--
作者：
Kataoka, Kosuke;Fujihashi, Kohtaro;Oishi, Kazunori
我们先前已经表明，含有编码Flt 3配体（FL）基因（pFL）的DNA质粒的基于肺炎球菌表面蛋白A（PspA）的疫苗作为鼻佐剂预防肺炎链球菌的鼻携带。在这项研究中，我们进一步研究了这种鼻疫苗诱导针对肺部感染的S.肺炎。用重组PspA/Rx 1（rPspA）加pFL以每周间隔鼻免疫C57 BL/6小鼠三次。当pFL的动态易位最初检查，鼻pFL采取了鼻树突状细胞（DC）和上皮细胞（nECs），但不是在中枢神经系统，包括嗅神经和上皮。重要的是，鼻pFL诱导FL蛋白的合成与最低水平的炎性细胞因子在鼻洗液（NW）和支气管肺泡灌洗液（BALF）。鼻rPspA + pFL给药小鼠的NW和BALF以及血浆中rPspA特异性分泌型伊加和IgG Ab应答水平升高，这与鼻粘膜相关淋巴组织（NALT）和颈部淋巴结（CLN）中CD 8（+）和CD 11b（+）DC以及产生白细胞介素2（IL-2）和IL-4的CD 4（+）T细胞数量升高相关。当小鼠用肺炎链球菌WU 2经鼻攻击时，rPspA特异性Abs的体内保护作用在肺、气道分泌物和血液中的CFU数量显著减少中是明显的。我们的研究结果表明，鼻pFL是一种安全有效的粘膜佐剂，通过DC诱导的Th 2型和IL-2细胞因子应答增强细菌抗原（Ag）（rPspA）特异性保护性免疫。
We have previously shown that a pneumococcal surface protein A (PspA)-based vaccine containing DNA plasmid encoding the Flt3 ligand (FL) gene (pFL) as a nasal adjuvant prevented nasal carriage of Streptococcus pneumoniae. In this study, we further investigated the safety and efficacy of this nasal vaccine for the induction of PspA-specific antibody (Ab) responses against lung infection with S. pneumoniae. C57BL/6 mice were nasally immunized with recombinant PspA/Rx1 (rPspA) plus pFL three times at weekly intervals. When dynamic translocation of pFL was initially examined, nasal pFL was taken up by nasal dendritic cells (DCs) and epithelial cells (nECs) but not in the central nervous systems, including olfactory nerve and epithelium. Of importance, nasal pFL induced FL protein synthesis with minimum levels of inflammatory cytokines in the nasal washes (NWs) and bronchoalveolar lavage fluid (BALF). NWs and BALF as well as plasma of mice given nasal rPspA plus pFL contained increased levels of rPspA-specific secretory IgA and IgG Ab responses that were correlated with elevated numbers of CD8(+) and CD11b(+) DCs and interleukin 2 (IL-2)- and IL-4-producing CD4(+) T cells in the nasal mucosa-associated lymphoid tissues (NALT) and cervical lymph nodes (CLNs). The in vivo protection by rPspA-specific Abs was evident in markedly reduced numbers of CFU in the lungs, airway secretions, and blood when mice were nasally challenged with Streptococcus pneumoniae WU2. Our findings show that nasal pFL is a safe and effective mucosal adjuvant for the enhancement of bacterial antigen (Ag) (rPspA)-specific protective immunity through DC-induced Th2-type and IL-2 cytokine responses.