IMMUNOLOGICAL PARAMETERS TO DEFINE INFECTION PROGRESSION AND THERAPY RESPONSE IN A WELL-DEFINED TUBERCULOSIS MODEL IN MICE
IMMUNOLOGICAL PARAMETERS TO DEFINE INFECTION PROGRESSION AND THERAPY RESPONSE IN A WELL-DEFINED TUBERCULOSIS MODEL IN MICE
复制标题
DOI：
10.1177/039463200902200318
复制
发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Bakker-Woudenberg, I. A. J. M.
中科院分区：
文献类型：
--
作者：
De Steenwinkel, J. E. M.;De Knegt, G. J.;Bakker-Woudenberg, I. A. J. M.
为了评估结核病诊断和治疗的新方法，需要经过良好验证的动物结核病模型。特别是耐药结核病的出现和传播需要创新的治疗方法和监测治疗成功或失败的准确参数。我们建立了BALB/c小鼠结核模型，通过自然呼吸道途径诱导结核分枝杆菌（Mtb）感染，模拟人类结核感染。在感染的第一阶段，肺部显示由肉芽肿组成的轻度炎症浸润，随后在慢性期，肺病变进行性增加，导致广泛的肺实变。观察到肺外部位播散。该模型在治疗结果方面得到了验证。按照人体药代动力学等效剂量进行的26周标准治疗导致所有感染器官中的结核分枝杆菌完全消除，治疗后没有感染复发。然而，13周的治疗，模拟患者的不依从性导致感染复发。在我们寻找监测治疗成功或失败的生物标志物的过程中，我们通过细胞细胞阵列（CBA）测定血清和肺中各种细胞因子的浓度，并通过免疫组织化学评估肺中细胞因子的原位表达。血清中ifn - γ浓度水平随着感染的进展而增加，在有效治疗期间下降，因此似乎是治疗成功或失败的适当免疫学参数。不适当治疗后感染复发表现为血清ifn - γ浓度升高。
To evaluate novel approaches for tuberculosis (TB) diagnostics and treatment, well-validated animal TB models are needed. Especially the emergence and spread of drug resistant TB requires innovative therapy and accurate parameters for monitoring success or failure of therapy. We developed a TB model in BALB/c mice, in which Mycobacterium tuberculosis (Mtb) infection was induced through the natural respiratory route, mimicking human TB infection. The lung showed a mild inflammatory infiltrate consisting of granulomas in the first phase of infection, followed by progressive increase of pneumonic lesions resulting in extensive lung consolidation in the chronic phase. Dissemination to the extra-pulmonary sites was observed. The model was validated in terms of therapeutic outcome. The 26-week standard therapy administered in human pharmacokinetic-equivalent doses, resulted in complete elimination of Mtb in all infected organs, without relapse of infection in the post-treatment period. However, a 13-week therapy, simulating patient non-adherence resulted in relapse of infection. In our quest to find biomarkers for monitoring success or failure of therapy, the concentrations of various cytokines in serum and lung, determined by Cytometric Bead Array (CBA), were evaluated in relation to the in situ cytokine expression in the lung, assessed by immunohistochemistry. The level of IFN-gamma concentration in serum increased with infection progression, and decreased during effective therapy, and as such appeared to be an appropriate immunological parameter for success or failure of therapy. Relapse of infection, after inappropriate therapy, manifested as an increase in the serum IFN-gamma concentration.