Hernandez-Pando R, Pavon L, Orozco E H, Rangel J, Rook G A
Experimental Pathology Laboratory, Department of Pathology, Instituto Nacional de la Nutricion 'Salvador Zubiran', Mexico City, Mexico.
Immunology. 2000 Jul;100(3):391-8. doi: 10.1046/j.1365-2567.2000.00054.x.
Problems of logistics, compliance and drug resistance point to an urgent need for immunotherapeutic strategies capable of shortening the current 6-month chemotherapy regimens used to treat tuberculosis, or of supplementing ineffective therapy. In this study we sought to define the mechanism of action of two immunotherapies, both of which have previously been shown to prolong survival. Secondly, we wished to identify any clinically useful synergy between these therapies. In BALB/c mice infected via the trachea with Mycobacterium tuberculosis H37Rv there is an initial phase of partial resistance dominated by type 1 cytokines plus tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), followed by a phase of progressive disease. This progressive phase is accompanied by increasing expression of IL-4, and diminished expression of IL-1 and TNF-alpha. Animals in this late progressive phase of the disease (day 60) were treated with two injections (day 60 and day 90) of 0.1 or 1.0 mg of heat-killed Mycobacterium vaccae, or with 3beta, 17beta-androstenediol (AED; 25 microg subcutaneously three times/week), or with both therapies. We show here using four techniques in parallel (morphometry, immunohistochemistry with automated cell counting, semiquantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays of cytokines in lung extracts) that treatment with M. vaccae causes a switch back towards a type 1 cytokine profile, restoration of expression of IL-1alpha and TNF-alpha, and a switch from pneumonia to granuloma. This is very similar to the changes previously seen after treatment with AED. However, there was no evidence for synergy between M. vaccae and AED.
物流、合规性和耐药性问题表明，迫切需要能够缩短目前用于治疗结核病的6个月化疗方案或补充无效治疗的免疫治疗策略。在本研究中，我们试图确定两种免疫疗法的作用机制，这两种疗法此前均已显示可延长生存期。其次，我们希望确定这些疗法之间是否存在任何临床上有用的协同作用。在通过气管感染结核分枝杆菌H37Rv的BALB/c小鼠中，存在一个由1型细胞因子加肿瘤坏死因子-α（TNF-α）和白细胞介素-1（IL-1）主导的初始部分抵抗阶段，随后是疾病进展阶段。这个进展阶段伴随着IL-4表达的增加以及IL-1和TNF-α表达的减少。处于疾病晚期进展阶段（第60天）的动物在第60天和第90天接受两次注射，分别注射0.1毫克或1.0毫克热灭活的母牛分枝杆菌，或注射3β,17β-雄烯二醇（AED；每周皮下注射3次，每次25微克），或同时接受两种疗法。我们在此同时使用四种技术（形态计量学、自动细胞计数免疫组织化学、半定量逆转录聚合酶链反应以及肺提取物中细胞因子的酶联免疫吸附测定）表明，用母牛分枝杆菌治疗会导致向1型细胞因子谱转变、IL-1α和TNF-α表达恢复以及从肺炎转变为肉芽肿。这与之前用AED治疗后观察到的变化非常相似。然而，没有证据表明母牛分枝杆菌和AED之间存在协同作用。
