De Steenwinkel J E M, De Knegt G J, Ten Kate M T, Van Belkum A, Verbrugh H A, Hernandez-Pando R, Van Soolingen D, Bakker-Woudenberg I A J M
Erasmus MC, University Medical Centre Rotterdam, Department of Medical Microbiology and Infectious Diseases, Rotterdam, The Netherlands.
Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):723-34. doi: 10.1177/039463200902200318.
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.
为了评估结核病（TB）诊断和治疗的新方法，需要经过充分验证的动物TB模型。尤其是耐药结核病的出现和传播，需要创新疗法以及用于监测治疗成败的准确参数。我们在BALB/c小鼠中建立了一种TB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TB感染。在感染的第一阶段，肺显示出由肉芽肿组成的轻度炎性浸润，随后肺部病变逐渐增加，在慢性期导致广泛的肺实变。观察到了肺外部位的播散。该模型在治疗效果方面得到了验证。以人体药代动力学等效剂量给予的26周标准疗法，导致所有感染器官中的Mtb被完全清除，治疗后期间未出现感染复发。然而，模拟患者不依从的13周疗法导致感染复发。在我们寻找监测治疗成败的生物标志物的过程中，通过细胞计数珠阵列（CBA）测定的血清和肺中各种细胞因子的浓度，与通过免疫组织化学评估的肺原位细胞因子表达相关联进行了评估。血清中IFN-γ浓度水平随感染进展而升高，在有效治疗期间降低，因此似乎是治疗成败的一个合适的免疫学参数。不适当治疗后感染复发表现为血清IFN-γ浓度升高。
