Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: Possible role for limiting pathology
Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: Possible role for limiting pathology
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DOI：
10.1128/iai.69.3.1847-1855.2001
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发表时间：
2001-03-01
影响因子：
3.1
通讯作者：
Chan, J
中科院分区：
文献类型：
--
作者：
Mohan, VP;Scanga, CA;Chan, J
潜伏性结核病的重新激活在很大程度上导致了结核分枝杆菌引起的疾病的发病率，但人们对遏制潜伏性结核病的机制知之甚少。使用小剂量持续性小鼠结核病模型和MP6-XT22，一种功能性中和肿瘤坏死因子-α的单抗，我们研究了肿瘤坏死因子-α在持续性和再激活结核感染中对宿主免疫反应的影响。研究结果证实了肿瘤坏死因子-α在遏制持续性结核病中的重要作用。肿瘤坏死因子-α中和导致致死性复活持续性肺结核，其特征是组织细菌负荷适度增加和严重的肺组织病理恶化，与表明肺泡腔内鳞状化生和液体堆积的变化有关。对低剂量模型小鼠肺组织基因和蛋白表达的分析表明，在MP6-XT22诱导的再激活过程中，一氧化氮合酶被减弱，但并未完全被抑制。IL-12p40和干扰素基因在肿瘤坏死因子-α中和组小鼠中的表达与对照组相似。相反，在肿瘤坏死因子-α中和的小鼠中，白介素10的表达增加。综上所述，本研究结果提示，肿瘤坏死因子-α在预防持续性结核的复活、调节特定免疫因子在肺组织中的表达、限制宿主的病理反应方面发挥了重要作用。
Reactivation of latent tuberculosis contributes significantly to the incidence of disease caused by Mycobacterium tuberculosis, The mechanisms involved in the containment of latent tuberculosis are poorly understood. Using the low-dose model of persistent murine tuberculosis in conjunction with MP6-XT22, a monoclonal antibody that functionally neutralizes tumor necrosis factor alpha (TNF-alpha), we examined the effects of TNF-alpha on the immunological response of the host in both persistent and reactivated tuberculous infections. The results confirm an essential role for TNF-alpha in the containment of persistent tuberculosis. TNF-alpha neutralization resulted in fatal reactivation of persistent tuberculosis characterized by a moderately increased tissue bacillary burden and severe pulmonic histopathological deterioration that was associated with changes indicative of squamous metaplasia and fluid accumulation in the alveolar space. Analysis of pulmonic gene and protein expression of mice in the low-dose model revealed that nitric oxide synthase was attenuated during MP6-XT22-induced reactivation, but was not totally suppressed. Interleukin-12p40 and gamma interferon gene expression in TNF-alpha -neutralized mice was similar to that in control mice. In contrast, interleukin-10 expression was augmented in the TNF-alpha -neutralized mice. In summary, results of this study suggest that TNF-alpha plays an essential role in preventing reactivation of persistent tuberculosis, modulates the pulmonic expression of specific immunologic factors, and limits the pathological response of the host.