Orally Administered Mycobacterium vaccae Modulates Expression of Immunoregulatory Molecules in BALB/c Mice with Pulmonary Tuberculosis
Orally Administered Mycobacterium vaccae Modulates Expression of Immunoregulatory Molecules in BALB/c Mice with Pulmonary Tuberculosis
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DOI：
10.1128/cvi.00286-08
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发表时间：
2008-11-01
影响因子：
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通讯作者：
Rook, Graham A.
中科院分区：
文献类型：
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作者：
Hernandez-Pando, Rogelio;Aguilar, Diana;Rook, Graham A.
环境腐生菌母牛分枝杆菌可诱导 Th1 反应和识别结核分枝杆菌的细胞毒性 T 细胞，通过皮下注射，可治疗 BALB/c 小鼠因高剂量攻击而诱发的肺结核 (TB)。然而，母牛分枝杆菌还驱动抑制 Th2 反应的调节性 T 细胞，这在过敏模型中可见，不仅在皮下注射后，而且在口服给药后也是如此。结核病的口服免疫疗法在临床上是有用的，因此我们研究了在结核病模型中每隔 28 天通过强饲法口服母牛分枝杆菌。我们使用了两种不同的方案：在结核分枝杆菌感染前 1 天或感染后 32 天开始口服母牛分枝杆菌。在整个感染过程中（直到 120 天），我们监测了结果 (CFU)、参与免疫调节发展的分子（Foxp3、血氧合酶 1、异羟胺 2,3-双加氧酶和转化生长因子 β [TGF-β]）以及细胞因子平衡指标（肿瘤坏死因子、诱导型一氧化氮合酶、白细胞介素 4 [IL-4] 和 IL-4 δ 2；一种抑制性细胞因子）。 IL-4 的剪接变体与人类结核病的改善结果相关）。口服母牛分枝杆菌对 CFU 有显着影响，导致 Th1 标记物和 IL-4 delta 2 的表达增加，同时抑制 IL-4、Foxp3 和 TGF-β。当在感染前 1 天给药时，口服母牛分枝杆菌诱导了血氧合酶 1 表达的惊人峰值。总之，我们展示了有关小鼠 IL-4 delta 2 和参与免疫调节的分子在结核病中表达的新信息，并表明这些可以通过口服腐生分枝杆菌进行调节。口服母牛分枝杆菌治疗广泛耐药结核病的临床试验可能是合理的。
The environmental saprophyte Mycobacterium vaccae induces a Th1 response and cytotoxic T cells that recognize M. tuberculosis, and by subcutaneous injection, it is therapeutic for pulmonary tuberculosis (TB) induced by high-dose challenge in BALB/c mice. However, M. vaccae also drives regulatory T cells that inhibit Th2 responses, and this is seen in allergy models, not only following subcutaneous injection but also after oral administration. An oral immunotherapeutic for TB would be clinically useful, so we investigated M. vaccae given orally by gavage at 28-day intervals in the TB model. We used two different protocols: starting the oral M. vaccae either 1 day before or 32 days after infection with M. tuberculosis. Throughout the infection (until 120 days), we monitored outcome (CFU), molecules involved in the development of immunoregulation (Foxp3, hemoxygenase 1, idoleamine 2,3-dioxygenase, and transforming growth factor beta [TGF-beta]), and indicators of cytokine balance (tumor necrosis factor, inducible nitric oxide synthase, interleukin-4 [IL-4], and IL-4 delta 2; an inhibitory splice variant of IL-4 associated with improved outcome in human TB). Oral M. vaccae had a significant effect on CFU and led to increased expression of Th1 markers and of IL-4 delta 2, while suppressing IL-4, Foxp3, and TGF-beta. When administered 1 day before infection, oral M. vaccae induced a striking peak of expression of hemoxygenase 1. In conclusion, we show novel information about the expression in TB of murine IL-4 delta 2 and molecules involved in immunoregulation and show that these can be modulated by oral administration of a saprophytic mycobacterium. A clinical trial of oral M. vaccae in extensively drug-resistant TB might be justified.