Stanford John, Stanford Cynthia, Grange John
Department of Medical Microbiology, University College London, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JK, United Kingdom.
Front Biosci. 2004 May 1;9:1701-19. doi: 10.2741/1292.
All the trials of immunotherapy of tuberculosis with killed Mycobacterium vaccae, published or not, that are known to the authors are reviewed here. Following an introduction giving a brief account of some earlier immunotherapies for tuberculosis, the origins of the concept of immunotherapy with M.vaccae are considered. Progress is traced from the early work with irradiation-killed organisms in leprosy to the study in London of modulation of tuberculin skin-test responses, and the first comparative trials in The Gambia and Kuwait. In the last of these studies, dosages and different preparations were compared. As a result of this subsequent studies have used 109 heat-killed organisms, equivalent to 1mg wet-weight of bacilli, as a standard dose. A series of small trials in Argentina, India, Nigeria, Romania, South Africa and Vietnam have pioneered the way forward, disclosing geographic variability, with South Africa as the only country where almost no effects were recorded. Together the studies have shown that a single dose may not be sufficient. These studies have confirmed the mode of action of M.vaccae to be regulation of cell-mediated immunity with enhancement of Th1 and down-regulation of Th2, and they have shown benefits in faster bacteriological conversion, reduction in ESR, recovery of body weight and resolution of radiological opacities, leading to better recovery from the disease even when given to patients receiving directly observed therapy, short-course (DOTS). Three major randomised, placebo-controlled and partly blinded trials have been carried out in Africa. The first, in South Africa showed no M.vaccae-related effects. The second trial, in Uganda, confirmed the observations made in the earlier studies of faster sputum conversion and better radiological clearance. The third trial, in Zambia and Malawi, showed a trend towards benefits in the treatment of HIV seronegative patients but failed to show beneficial effects in HIV seropositive patients. Studies in patients with multi-drug-resistant tuberculosis have shown that multiple doses of immunotherapy are required in most cases, and that these markedly improve cure-rates for these patients. This is especially so when they are also treated with chemotherapy tailored to the resistance pattern of their infecting organisms. A small study has just commenced in which repeated doses of M.vaccae are being administered to a group of patients who have failed treatment with DOTS-Plus (directly observed therapy with drugs selected on the basis of drug susceptibility profiles). Late in the investigation came publications from China supporting and confirming the data in both drug-sensitive and drug-resistant disease, by the use of multiple injections of their own different preparation of M.vaccae. The trial that is now beginning in Vietnam of 3 doses of M.vaccae in the treatment of newly diagnosed pulmonary tuberculosis, is accompanied by a chemotherapeutic regimen with a shortened continuation phase. If this important study is successful, immunotherapy with killed M.vaccae should be introduced into the treatment regimens for tuberculosis worldwide.
本文回顾了所有已发表或未发表的、作者已知的用灭活母牛分枝杆菌进行结核病免疫治疗的试验。在引言部分简要介绍了一些早期的结核病免疫治疗方法后，探讨了母牛分枝杆菌免疫治疗概念的起源。追溯了从麻风病中使用辐照灭活菌的早期研究，到伦敦对结核菌素皮肤试验反应调节的研究，以及在冈比亚和科威特进行的首次比较试验的进展。在这些研究的最后一项中，比较了剂量和不同制剂。基于此，后续研究采用109个热灭活菌，相当于1毫克湿重的杆菌，作为标准剂量。阿根廷、印度、尼日利亚、罗马尼亚、南非和越南的一系列小型试验开创了前进的道路，揭示了地理差异，南非是几乎未记录到任何效果的唯一国家。这些研究共同表明，单剂量可能不够。这些研究证实了母牛分枝杆菌的作用方式是调节细胞介导的免疫，增强Th1并下调Th2，并且显示出在更快的细菌学转化、红细胞沉降率降低、体重恢复和放射学不透明度消退方面的益处，即使给予接受直接观察治疗短程疗法（DOTS）的患者，也能使疾病更好地康复。在非洲进行了三项主要的随机、安慰剂对照且部分设盲的试验。第一项在南非进行，未显示出与母牛分枝杆菌相关的效果。第二项试验在乌干达进行，证实了早期研究中更快的痰菌转化和更好的放射学清除的观察结果。第三项试验在赞比亚和马拉维进行，显示出在治疗HIV血清阴性患者时有获益趋势，但在HIV血清阳性患者中未显示出有益效果。对耐多药结核病患者的研究表明，大多数情况下需要多次免疫治疗剂量，并且这些剂量能显著提高这些患者的治愈率。当同时根据感染菌的耐药模式进行化疗时尤其如此。一项小型研究刚刚开始，对一组接受DOTS-Plus（根据药物敏感性谱选择药物进行直接观察治疗）治疗失败的患者给予重复剂量的母牛分枝杆菌。在研究后期，中国发表了支持和证实药物敏感和耐药疾病数据的文章，他们使用了自己不同制剂的多次注射。越南目前正在开展一项用3剂母牛分枝杆菌治疗新诊断肺结核的试验，同时采用缩短继续期的化疗方案。如果这项重要研究取得成功，用灭活母牛分枝杆菌进行免疫治疗应被引入全球结核病的治疗方案中。
