Effects of DNA- and Mycobacterium bovis BCG-Based Delivery of the Flt3 Ligand on Protective Immunity to Mycobacterium tuberculosis-猫眼课题宝

基于 DNA 和牛分枝杆菌 BCG 的 Flt3 配体递送对结核分枝杆菌保护性免疫的影响

DOI：

10.1128/iai.00322-07

发表时间：

2007

期刊：

Infection and Immunity

影响因子：

3.1

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

J. Triccas;E. Shklovskaya;Joanne M. Spratt;A. Ryan;U. Palendira;Barbara Fazekas de StGroth;W. Britton

结核分枝杆菌等细胞内病原体的控制依赖于病原体反应性T细胞的激活和维持。树突状细胞（Dendritic cells，DC）是体内启动抗分枝杆菌T细胞应答的主要抗原呈递细胞。为了研究旨在优化DC功能的免疫策略是否可以提高针对毒性分枝杆菌感染的保护性免疫，我们利用造血生长因子Fms样酪氨酸激酶3配体（Flt 3L）在体内扩增DC数量的能力。将编码小鼠Flt 3L和M.结核抗原85 B刺激T细胞释放γ-干扰素（IFN-γ），并提供更好的抗毒性M.结核病比DNA编码的单一成分。与仅用BCG免疫相比，用分泌Flt 3L的重组牛分枝杆菌BCG菌株（BCG：Flt 3L）免疫小鼠导致DC的早期扩增，并且该效应与BCG反应性IFN-γ分泌性T细胞的刺激增加有关。BCG和BCG：Flt 3L对低剂量气雾剂M的保护作用相似。然而，免疫缺陷小鼠的免疫显示BCG：Flt 3L的毒性明显低于常规BCG。这些结果证明了体内靶向DC以提高抗分枝杆菌疫苗效力的潜力。

ABSTRACT The control of intracellular pathogens such as Mycobacterium tuberculosis is dependent on the activation and maintenance of pathogen-reactive T cells. Dendritic cells (DCs) are the major antigen-presenting cells initiating antimycobacterial T-cell responses in vivo. To investigate if immunization strategies that aim to optimize DC function can improve protective immunity against virulent mycobacterial infection, we exploited the ability of the hematopoietic growth factor Fms-like tyrosine kinase 3 ligand (Flt3L) to expand the number of DCs in vivo. A DNA fusion of the genes encoding murine Flt3L and M. tuberculosis antigen 85B stimulated enhanced gamma interferon (IFN-γ) release by T cells and provided better protection against virulent M. tuberculosis than DNA encoding the single components. Vaccination of mice with a recombinant Mycobacterium bovis BCG strain secreting Flt3L (BCG:Flt3L) led to early expansion of DCs compared to immunization with BCG alone, and this effect was associated with increased stimulation of BCG-reactive IFN-γ-secreting T cells. BCG and BCG:Flt3L provided similar protective efficacies against low-dose aerosol M. tuberculosis; however, immunization of immunodeficient mice revealed that BCG:Flt3L was markedly less virulent than conventional BCG. These results demonstrate the potential of in vivo targeting of DCs to improve antimycobacterial vaccine efficacy.