Lethal granuloma disintegration in mycobacteria-infected TNFRp55-/- mice is dependent on T cells and IL-12
Lethal granuloma disintegration in mycobacteria-infected TNFRp55-/- mice is dependent on T cells and IL-12
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DOI：
10.4049/jimmunol.165.1.483
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发表时间：
2000-07-01
影响因子：
4.4
通讯作者：
Pfeffer, K
中科院分区：
文献类型：
--
作者：
Ehlers, S;Kutsch, S;Pfeffer, K
基因易感的TNFRp55基因缺陷(TNFRp55(-/-))小鼠死于禽分枝杆菌感染，在它们死亡之前，感染禽分枝杆菌的TNFRp55(-/-)小鼠会出现肉芽肿病变，与野生型同基因小鼠的肉芽肿不同，它们会经历急性解体。为了确定与这些事件有关的因素，我们在静脉感染TNFRp55(-/-)的小鼠中耗尽T细胞亚群或中和炎性细胞因子干扰素-γ、IL-12或肿瘤坏死因子。带M的是Avium。用对照单抗治疗的受感染的TNFRp55(-/-)小鼠在感染后26到34天内死亡，在解体肉芽肿内显示广泛的炎性细胞凋亡。相反，在肉芽肿开始后，去除了CD4(+)或CD8(+)细胞的TNFRp55(-/-)小鼠至少在感染后第38天仍保持健康，并且没有表现出肉芽肿破坏的迹象。中和IL-12，但不中和干扰素-γ或肿瘤坏死因子，也能保护HI。禽类感染TNFRp55(-/-)小鼠，来自肉芽肿分解和过早死亡。地塞米松或诱导型一氧化氮合酶的特异性抑制剂治疗不能阻止TNFRp55(-/-)小鼠肉芽肿的溶解或死亡。总之，TNFRp55(-/-)小鼠肉芽肿的解体是一个依赖于IL-12的致命性事件，它是由过剩的T细胞介导的。
Genetically susceptible, TNFRp55 gene-deficient (TNFRp55(-/-)) mice succumb to infection with Mycobacterium avium, Before their death, M. avium-infected TNFRp55(-/-) mice develop granulomatous lesions that, in contrast to granulomas in wild-type syngeneic mice, undergo acute disintegration. To determine the factors involved in these events, we depleted T cell subsets or neutralized the inflammatory cytokines IFN-gamma, IL-12, or TNF in TNFRp55(-/-) mice infected i.v. with M, avium. Infected TNFRp55(-/-) mice treated with a control mAb became moribund between days 26 and 34 postinfection, showing widespread inflammatory cell apoptosis within disintegrating granulomas. In contrast, TNFRp55(-/-) mice depleted of either CD4(+) or CD8(+) cells after granuloma initiation stayed healthy until at least day 38 postinfection and showed no signs of granuloma destruction. Neutralization of IL-12, but not of IFN-gamma or TNF, also protected hi. avium-infected TNFRp55(-/-) mice from granuloma decomposition and from premature death. Treatment with dexamethasone or with a specific inhibitor of inducible NO synthase did not prevent granuloma dissolution or death of TNFRp55(-/-) mice. In conclusion, granuloma disintegration in TNFRp55(-/-) mice is a lethal event that is dependent on IL-12 and that is mediated by an excess of T cells.