Induction of a specific strong polyantigenic cellular immune response after short-term chemotherapy controls bacillary reactivation in murine and guinea pig experimental models of tuberculosis
Induction of a specific strong polyantigenic cellular immune response after short-term chemotherapy controls bacillary reactivation in murine and guinea pig experimental models of tuberculosis
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DOI：
10.1128/cvi.00094-08
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发表时间：
2008-08-01
影响因子：
--
通讯作者：
Cardona, Pere-Joan
中科院分区：
文献类型：
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作者：
Guirado, Evelyn;Gil, Olga;Cardona, Pere-Joan
鲁蒂是一种治疗性疫苗，由解毒和脂质体化的结核分枝杆菌细胞片段产生，已证明其在控制短期化疗后的芽孢杆菌再活化方面的功效。本研究的目的是表征鲁蒂治疗性给药后产生的细胞免疫应答，并证实疫苗无毒性。用小剂量M.肺结核气雾剂在两种实验模型中，RUTI治疗的动物显示出最低的细菌负荷。鲁蒂还降低小鼠和豚鼠模型中肺肉芽肿浸润的百分比。而牛分枝杆菌BCG治疗后情况并非如此。用M.结核特异性结构和生长相关抗原。我们的数据显示BCG和鲁蒂治疗性给药之间的差异主要在于IFN-γ（+）CD 4（+）细胞和CD 8（+）细胞对结核菌素纯化蛋白衍生物、ESAT-6和鲁蒂产生的Ag 85 B的更强活化。两种疫苗都能引发针对M.结核结构抗原Ag 16 kDa和Ag 38 kDa以及IFN-γ、肿瘤坏死因子、白细胞介素-12、诱导型一氧化氮合酶和RANTES在肺中的显著mRNA表达。结果表明，鲁蒂的治疗效果不仅与诱导Th 1应答有关，而且还与刺激更快和更强的针对结构和生长相关抗原的特异性免疫有关，从而减少细菌负荷和肺部病理。
RUTI is a therapeutic vaccine that is generated from detoxified and liposomed Mycobacterium tuberculosis cell fragments that has demonstrated its efficacy in the control of bacillus reactivation after short-term chemotherapy. The aim of this study was to characterize the cellular immune response generated after the therapeutic administration of RUTI and to corroborate the lack of toxicity of the vaccine. Mouse and guinea pig experimental models were infected with a low-dose M. tuberculosis aerosol. RUTI-treated animals showed the lowest bacillary load in both experimental models. RUTI also decreased the percentage of pulmonary granulomatous infiltration in the mouse and guinea pig models. This was not the case after Mycobacterium bovis BCG treatment. Cellular immunity was studied through the characterization of the intracellular gamma interferon (IFN-gamma)-producing cells after the splenocytes' stimulation with M. tuberculosis-specific structural and growth-related antigens. Our data show that the difference between the therapeutic administration of BCG and RUTI resides mainly in the stronger activation of IFN-gamma(+) CD4(+) cells and CD8(+) cells against tuberculin purified protein derivative, ESAT-6, and Ag85B that RUTI generates. Both vaccines also triggered a specific immune response against the M. tuberculosis structural antigens Ag16kDa and Ag38kDa and a marked mRNA expression of IFN-gamma, tumor necrosis factor, interleukin-12, inducible nitric oxide synthase, and RANTES in the lung. The results show that RUTI's therapeutic effect is linked not only to the induction of a Th1 response but also to the stimulation of a quicker and stronger specific immunity against structural and growth-related antigens that reduces both the bacillary load and the pulmonary pathology.