Ordonez Alvaro A, Pokkali Supriya, DeMarco Vincent P, Klunk Mariah, Mease Ronnie C, Foss Catherine A, Pomper Martin G, Jain Sanjay K
Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2015 Jan;59(1):642-9. doi: 10.1128/AAC.04180-14. Epub 2014 Nov 17.
Current tools for monitoring response to tuberculosis treatments have several limitations. Noninvasive biomarkers could accelerate tuberculosis drug development and clinical studies, but to date little progress has been made in developing new imaging technologies for this application. In this study, we developed pulmonary single-photon emission computed tomography (SPECT) using radioiodinated DPA-713 to serially monitor the activity of tuberculosis treatments in live mice, which develop necrotic granulomas and cavitary lesions. C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered either a standard or a highly active bedaquiline-containing drug regimen. Serial (125)I-DPA-713 SPECT imaging was compared with (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and standard microbiology. Ex vivo studies were performed to characterize and correlate DPA-713 imaging with cellular and cytokine responses. Pulmonary (125)I-DPA-713 SPECT, but not (18)F-FDG PET, was able to correctly identify the bactericidal activities of the two tuberculosis treatments as early as 4 weeks after the start of treatment (P < 0.03). DPA-713 readily penetrated the fibrotic rims of necrotic and cavitary lesions. A time-dependent decrease in both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels was observed with treatments, with (125)I-DPA-713 SPECT correlating best with tissue TNF-α levels (ρ = 0.94; P < 0.01). (124)I-DPA-713 was also evaluated as a PET probe and demonstrated a 4.0-fold-higher signal intensity in the infected tuberculous lesions than uninfected controls (P = 0.03). These studies provide proof of concept for application of a novel noninvasive imaging biomarker to monitor tuberculosis treatments, with the potential for application for humans.
目前用于监测结核病治疗反应的工具存在若干局限性。非侵入性生物标志物可加速结核病药物研发和临床研究，但迄今为止，针对该应用开发新的成像技术进展甚微。在本研究中，我们利用放射性碘化DPA - 713开发了肺部单光子发射计算机断层扫描（SPECT）技术，以连续监测感染结核分枝杆菌并形成坏死性肉芽肿和空洞性病变的活体小鼠体内结核病治疗的活性。将C3HeB/FeJ小鼠经气溶胶感染结核分枝杆菌，并给予标准或含高活性贝达喹啉的药物治疗方案。将系列（125）I - DPA - 713 SPECT成像与（18）F - 氟脱氧葡萄糖（（18）F - FDG）正电子发射断层扫描（PET）及标准微生物学方法进行比较。进行了体外研究，以表征DPA - 713成像并将其与细胞和细胞因子反应相关联。肺部（125）I - DPA - 713 SPECT而非（18）F - FDG PET能够在治疗开始后4周就正确识别两种结核病治疗的杀菌活性（P < 0.03）。DPA - 713很容易穿透坏死和空洞性病变的纤维化边缘。治疗过程中观察到肿瘤坏死因子α（TNF - α）和干扰素γ（IFN - γ）水平随时间下降，其中（125）I - DPA - 713 SPECT与组织TNF - α水平相关性最佳（ρ = 0.94；P < 0.01）。（124）I - DPA - 713也被评估为一种PET探针，结果显示感染结核病变中的信号强度比未感染对照高4.0倍（P = 0.03）。这些研究为应用新型非侵入性成像生物标志物监测结核病治疗提供了概念验证，具有应用于人类的潜力。
