Correction of defective host response to Mycobacterium bovis BCG infection in TNF-deficient mice by bone marrow transplantation
Correction of defective host response to Mycobacterium bovis BCG infection in TNF-deficient mice by bone marrow transplantation
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DOI：
10.1038/labinvest.3780094
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发表时间：
2000-06-01
影响因子：
5
通讯作者：
Ryffel, B
中科院分区：
文献类型：
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作者：
Jacobs, M;Marino, MW;Ryffel, B
肿瘤坏死因子-α（TNF）在分枝杆菌感染中单核细胞的募集和活化中起着核心作用。在缺乏1型TNF受体的情况下，牛分枝杆菌卡介苗（BCG）感染的小鼠得不到遏制，导致致死性疾病。由于1型TNF受体结合TNF和α-光毒素，我们使用TNF缺陷小鼠来确定TNF在宿主抵抗BCG感染中的特定作用。TNF缺陷小鼠肺部的细菌负荷显著增加，小鼠在8至12周之间死于肺炎，并伴有缺陷性肉芽肿反应。4周时非典型肉芽肿形成，表达低水平的MHC II类分子、细胞内粘附分子（ICAM-1）、CD 11b和CD 11 c。巨噬细胞几乎没有活化迹象，酸性磷酸酶活性和诱导型一氧化氮合酶（INOS）表达水平低。尽管有缺陷的细胞募集，趋化因子，单核细胞趋化蛋白-1（MCP-1）和巨噬细胞炎性蛋白-1（MIP-1 α），在TNF-缺陷小鼠的支气管肺泡灌洗液中增加。通过将正常骨髓细胞移植到受辐射的TNF缺陷小鼠中来纠正有缺陷的宿主反应。这些结果表明，TNF来源于造血细胞，而不是从间充质来源是必不可少的正常宿主对BCG感染的反应。此外，TNF依赖的粘附分子的表达可能是必要的招募单核细胞形成杀菌BCG肉芽肿。
Tumour necrosis factor-alpha (TNF) plays a central role in the recruitment and activation of mononuclear cells in mycobacterial infection. In the absence of type 1 TNF receptor, Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection of mice is not contained, leading to fatal disease. Because type 1 TNF receptor binds both TNF and lymphotoxin-alpha, we used TNF-deficient mice to determine the specific role of TNF in the host resistance to BCG infection. The bacterial burden of the lungs of TNF-deficient mice was substantially increased and the mice succumbed to pneumonia between 8 and 12 weeks with a defective granuloma response. Atypical granulomas developed by 4 weeks expressing tow levels of MHC class II, intracellular adhesion molecule (ICAM-1), CD11b and CD11c. Macrophages showed little signs of activation and had low levels of acid phosphatase activity and inducible nitric oxide synthase (INOS) expression. Despite the defective cellular recruitment, the chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1 alpha), were increased in broncho-alveotar lavage fluid of TNF-deficient mice. The defective host response was corrected by the transplantation of normal bone marrow cells into irradiated TNF-deficient mice. These results demonstrate that TNF derived from hemopoietic cells rather than from mesenchymal origin are essential for a normal host response to BCG infection. Furthermore, TNF dependent expression of adhesion molecules may be essential for the recruitment of mononuclear cells for the formation of bactericidal BCG granulomas.