RUTI: A new chance to shorten the treatment of latent tuberculosis infection
RUTI: A new chance to shorten the treatment of latent tuberculosis infection
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DOI：
10.1016/j.tube.2006.01.024
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发表时间：
2006-05-01
期刊：
影响因子：
3.2
通讯作者：
Cardona, Pere-Joan
中科院分区：
文献类型：
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作者：
Cardona, Pere-Joan
潜伏性结核感染（LTBI）的治疗需要长时间的化疗（9个月），这使得治疗依从性非常困难。目前对潜伏性杆菌及其相关病变的了解表明，这些杆菌在肉芽肿中存活，中央坏死核心和最外层泡沫巨噬细胞（FM）是重要的免疫抑制屏障。FM的存在，在小鼠中特别强，不仅解释了死亡杆菌、碎片和表面活性剂排出的动力学，而且还解释了潜伏的杆菌如何从肉芽肿中逃逸并在周围重新生长，特别是在它们可以容易地扩散的肺泡空间中。鲁蒂，一种由解毒的、碎片化的结核分枝杆菌细胞制成的治疗性疫苗，以脂质体递送，评价其在短期化疗（1个月）中的疗效。这种疗法的基本原理首先是利用化疗的杀菌特性杀死活性生长的杆菌，消除FM的最外层并减少局部炎症反应，从而避免治疗时由A型结核抗原引起的可预测的Koch现象。化疗后，可接种鲁蒂以减少剩余潜伏杆菌再生长的可能性。鲁蒂已在小鼠和豚鼠的实验模型中证实了其在短期化疗后控制LTBI的有效性;这些动物实验显示诱导混合的Th 1/Th 2/Th 3多抗原应答，而无局部或全身毒性。特异性CD 8 T细胞的局部积累和强烈的体液应答是鲁蒂的特征性特征，这解释了其保护特性;当与BCG相比时，这些是特别的改进，尽管对鲁蒂的调节应答也可能是重要的优势。在开始I期临床试验之前，使用更大动物（山羊和小型猪）的进一步实验将提供更多关于鲁蒂疗效的数据。(c)2006爱思唯尔有限公司版权所有。
Treatment of latent tuberculosis infection (LTBI) requires a long period of chemotherapy (9 months), which makes treatment-comptiance extremely difficult. Current knowledge of latent bacilli and of the lesions with which they are associated suggests that these bacilli survive in granulomas with a central necrotic core and an outermost layer of foamy macrophages (FM) that represent an important immunosuppressive barrier. The presence of FM, which is especially strong in mice, explains not only the kinetics of the drainage of dead bacilli, debris and surfactant, but also how latent bacilli can escape from the granuloma and re-grow in the periphery, particularly in the alveolar spaces where they can disseminate easily.RUTI, a therapeutic vaccine made of detoxified, fragmented Mycobacterium tuberculosis cells, delivered in liposomes, was used to assess its effectiveness in a short period of chemotherapy (1 month). The rationale of this therapy was first to take advantage of the bactericidal properties of chemotherapy to kill active growing bacilli, eliminate the outermost layer of FM and reduce local inflammatory responses so as to avoid the predictable Koch phenomenon caused by A tuberculosis antigens when given therapeutically. After chemotherapy, RUTI can be inoculated to reduce the probability of regrowth of the remaining latent bacilli.RUTI has already demonstrated its efficacy in controlling LTBI in experimental models of mice and guinea-pigs after a short period of chemotherapy; these experiments in animals showed the induction of a mixed Th1/Th2/Th3, potyantigenic response with no local or systemic toxicity. Local accumulation of specific CD8 Tcells and a strong humoral response are characteristic features of RUTI that explain its protective properties; these are particular improvements when compared with BCG, although the regulatory response to RUTI may also be an important advantage. Further experiments using bigger animals (goats and mini-pigs) will provide more data on the efficacy of RUTI before starting phase I clinical trials. (c) 2006 Elsevier Ltd. All rights reserved.