Imaging immune-mediated liver rejection with Positron Emission Tomography

 描述(申请人提供)：同种异体肝移植排斥反应是肝移植后的一个重要问题。高达%的肝移植患者至少有一次肝脏免疫攻击，这通常是通过侵入性肝活检诊断，并使用越来越多的免疫抑制药物治疗。老年患者的肝活检由于合并疾病而变得复杂，免疫抑制剂增加了老年人出现有害副作用的风险。在肝移植排斥反应过程中无创监测免疫系统和肝脏的新方法以及免疫抑制剂的治疗可能对肝移植术后有显著的益处。正电子发射断层扫描(PET)是一种非侵入性的成像技术，可以在体内显示特定的细胞群，可能成为监测肝移植排斥反应的一种新方法。我们之前已经发现，18F-FDG和18F-FAC PET成像探针可以用来可视化和量化自身免疫性疾病、免疫介导的肿瘤排斥反应和免疫抑制药物治疗后免疫系统的活动。进一步的研究表明，18F-FDG和18F-FAC信号代表了特定和不同的免疫细胞群的活性。最后，我们有初步证据表明，PET成像探针18F-DFA可以用于体内肝细胞功能的量化，包括在肝脏免疫攻击期间。在这里，我们建议验证临床前的所有假设，即18F-FDG、18F-FAC或18F-DFA的PET成像可以用于有效、非侵入性和灵敏地监测免疫介导的肝排斥反应，并促进免疫抑制药物的滴定。这一假设将通过两个实验目标来验证：(1)在使用小鼠模型评估肝脏免疫排斥和免疫抑制药物治疗方面，18F-FDG、18F-FAC和18F-DFA的PET成像将与传统的血浆测量和肝脏组织病理学进行比较。(2)将确定在免疫介导的肝排斥反应过程中18F-FDG、18F-FAC和18F-DFA积聚变化的细胞类型特定事件。我们预计，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，这些成像探针在体内的生物分布和信号强度将发生变化。我们期望这项建议中的实验将提供证据，证明PET成像可用于非侵入性监测肝移植后的同种异体肝移植排斥反应和免疫抑制药物治疗。

 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.