Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a major global health problem. Lung granulomas are organized structures of host immune cells that function to contain the bacteria. Cytokine expression is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate TB. Although the importance of proinflammatory cytokines in controlling M. tuberculosis infection has been established, the effects of anti-inflammatory cytokines, such as IL-10, in TB are less well understood. To investigate the role of IL-10, we used an Ab to neutralize IL-10 in cynomolgus macaques during M. tuberculosis infection. Anti-IL-10-treated nonhuman primates had similar overall disease outcomes compared with untreated control nonhuman primates, but there were immunological changes in granulomas and lymph nodes from anti-IL-10-treated animals. There was less thoracic inflammation and increased cytokine production in lung granulomas and lymph nodes from IL-10-neutralized animals at 3-4 wk postinfection compared with control animals. At 8 wk postinfection, lung granulomas from IL-10-neutralized animals had reduced cytokine production but increased fibrosis relative to control animals. Although these immunological changes did not affect the overall disease burden during the first 8 wk of infection, we paired computational modeling to explore late infection dynamics. Our findings support that early changes occurring in the absence of IL-10 may lead to better bacterial control later during infection. These unique datasets provide insight into the contribution of IL-10 to the immunological balance necessary for granulomas to control bacterial burden and disease pathology in M. tuberculosis infection.

译文

结核分枝杆菌引起的结核病(TB)仍然是全球主要的健康问题。肺肉芽肿是宿主免疫细胞的组织结构,其功能是遏制细菌。细胞因子的表达是保护性免疫反应的关键组成部分,但是不适当的细胞因子表达会加剧结核病。尽管已经确定了促炎细胞因子在控制结核分枝杆菌感染中的重要性,但人们对抗炎细胞因子(如IL-10)在结核病中的作用还知之甚少。为了研究IL-10的作用,我们在结核分枝杆菌感染期间使用了Ab中和猕猴猕猴中的IL-10。与未经治疗的对照非人类灵长类动物相比,抗IL-10-处理的非人类灵长类动物具有相似的总体疾病结局,但抗IL-10处理的动物的肉芽肿和淋巴结免疫学改变。与对照动物相比,在感染后3-4周,IL-10中和动物的肺肉芽肿和淋巴结中的胸腔炎症减少,细胞因子产生增加。感染后第8周,来自IL-10中和动物的肺肉芽肿与对照动物相比,细胞因子产生减少,但纤维化增加。尽管这些免疫学变化在感染的前8周内并未影响总体疾病负担,但我们将计算模型配对以探讨晚期感染动态。我们的发现支持在缺乏IL-10的情况下发生早期变化可能会在感染后期导致更好的细菌控制。这些独特的数据集可洞察IL-10对肉芽肿控制结核分枝杆菌感染中细菌负担和疾病病理所必需的免疫平衡的贡献。

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