Imaging immune-mediated liver rejection with Positron Emission Tomography

 描述（由申请人提供）：肝移植排斥反应是肝移植后的一个重要问题。高达64%的肝移植患者至少有一次肝脏免疫攻击发作，通常通过侵入性肝活检进行诊断，并使用增加剂量的免疫抑制药物进行治疗。由于合并症，老年患者的肝活检很复杂，免疫抑制剂增加了老年患者有害副作用的风险。在肝移植排斥反应期间非侵入性监测免疫系统和肝脏的新方法及其免疫抑制剂治疗可能在肝移植后具有显着的益处。正电子发射断层扫描（PET）是一种非侵入性成像技术，可以在体内观察特定的细胞群，并可能代表一种新的方法来监测肝移植排斥反应。我们之前已经发现，PET成像探针18F-FDG和18F-FAC可用于在自身免疫性疾病、免疫介导的肿瘤排斥反应和免疫抑制药物治疗后观察和量化免疫系统的活性。另外的研究表明，18F-FDG和18F-FAC信号代表特异性和不同免疫细胞群体的活性。最后，我们有初步证据表明，PET成像探针18F-DFA可用于量化体内肝细胞功能，包括在肝脏免疫攻击期间。在这里，我们建议临床前测试的假设，PET显像与18 F-FDG，18 F-FAC，或18 F-DFA可以利用有效的，非侵入性的，和灵敏的监测免疫介导的肝脏排斥反应，并促进滴定的免疫抑制药物。该假设将通过两个实验目的进行测试：（1）在使用小鼠模型评估肝脏的免疫排斥和免疫抑制药物治疗时，将使用18F-FDG、18F-FAC和18F-DFA的PET成像与传统的血浆测量和肝脏组织病理学进行比较和对比。(2)将确定在免疫介导的肝排斥反应期间导致18F-FDG、18F-FAC和18F-DFA蓄积变化的细胞类型特异性事件。我们预计，这些成像探针的体内生物分布和信号强度将在免疫介导的肝排斥反应的不同阶段和免疫抑制剂治疗后发生改变。我们期望本提案中的实验将提供证据证明PET成像可用于无创监测肝移植排斥反应和肝移植后的免疫抑制药物治疗。

 DESCRIPTION (provided by applicant): Hepatic allograft rejection is a significant problem following liver transplants. Up to 64% of liver transplant patients suffer from at least one episod of immune attack on the liver, which is often diagnosed through invasive liver biopsies and treated with increasing doses of immunosuppressive drugs. Liver biopsies are complicated in elderly patients due to comorbidities, and immunosuppressants have increased risks of deleterious side effects in the elderly. New methods to non-invasively monitor the immune system and the liver during hepatic allograft rejection and its treatment with immunosuppressants could be of significant benefit following liver transplants. Positron emission tomography (PET) is a non-invasive imaging technology that allows for the visualization of specific cell populations in vivo and could represent a new approach for monitoring hepatic allograft rejection. We have previously found that the PET imaging probes 18F-FDG and 18F-FAC can be used to visualize and quantify the activity of the immune system during autoimmune disease, immune-mediated tumor rejection, and following treatment with immunosuppressive drugs. Additional studies demonstrated that 18F-FDG and 18F- FAC signal represents the activity of specific and distinct immune cell populations. Finally we have preliminary evidence that the PET imaging probe 18F-DFA can be used to quantify hepatocyte function in vivo, including during immune attack of the liver. Here we propose to test preclinicall the hypothesis that PET imaging with 18F-FDG, 18F-FAC, or 18F-DFA could be leveraged for effective, non-invasive, and sensitive monitoring of immune-mediated liver rejection and facilitate titration of immunosuppressive drugs. This hypothesis will be tested through two experimental aims: (1) PET imaging with 18F-FDG, 18F-FAC, and 18F-DFA will be compared to and contrasted with traditional plasma measurements and liver histopathology in assessing immune rejection of the liver and immunosuppressive drug treatments using mouse models. (2) Cell-type specific events that account for changes in 18F-FDG, 18F-FAC, and 18F-DFA accumulation during immune-mediated liver rejection will be identified. We anticipate that the in vivo biodistribution and signal intensity of these imaging probes will be altered during different stages of immune-mediated liver rejection and following treatment with immunosuppressants. We expect that the experiments in this proposal will provide evidence that PET imaging can be used to non- invasively monitor hepatic allograft rejection and immunosuppressive drug treatments following liver transplant.