Imaging Costimulation Blockade Resistant Rejection

摘要 目前，在临床实践中，急性排斥反应的检测通常依赖于血清实验室指标，如 如血清肌酐或肝功能测试，往往是对器官不敏感和非特异性的衡量标准 受伤。最终，排斥的诊断需要对移植器官进行针吸活组织检查。这种侵入性 手术与增加的成本和潜在的并发症相关，包括对邻近器官的损伤， 出血和移植物丢失。此外，移植物活检受到抽样误差的限制，其中不到0.01%的 检查同种异体移植，以及在解释结果时观察者间的可变性。患者经常 需要多次活检来评估治疗反应，从而使他们每次接受 单独的程序。最近，在非侵入性技术的发展方面有了很大的努力 检测排斥反应的方法包括基因表达谱分析和血、尿标本的基因组分析。 尽管最近有影响很大的报告，但这一战略尚未得到广泛采用。在这里，我们建议开发和 测试非侵入性成像技术，以监测对移植器官的同种异体免疫反应。 具体地说，我们将利用免疫PET来跟踪和表征CD28设置中的T细胞反应 共刺激阻断体内。我们将在小鼠模型中使用最先进的技术来研究这两个 幼稚和记忆T细胞反应，在那里我们将更好地定义共刺激阻断的机制 抵抗性排斥。重要的是，我们在小鼠和NHP模型中的初步数据揭示了CD122的关键作用 在促进共刺激阻断抵抗反应方面；因此，我们将使用免疫PET来可视化 移植后CD122+T细胞聚集的时空模式。我们还建议使用 免疫PET在我们的非人灵长类肾脏移植模型中的应用，以进一步了解 临床相关的共刺激作用、阻断抵抗排斥反应和评估临床可转译性。宠物已经是 广泛用于患者，在这种临床前环境下开发的技术可以直接应用于临床 练习一下。这种跨学科的应用结合了两名研究人员的专业知识：桑坦格罗博士，他 使用最先进的技术为免疫反应成像带来非凡的体验，例如 免疫PET和亚当斯博士带来了临床经验和对新型抗肿瘤药物的广泛理解 移植中的排斥治疗，包括共刺激阻断。这种强大的成像技术的使用 技术与新型免疫疗法的结合代表了一种高度创新的方法，以进一步推动我们的 对移植后同种异体免疫反应的理解。此外，评估的能力 这项技术不仅在啮齿类动物身上，而且在临床前非人类灵长类动物移植模型中也提供了一种明确的 预测患者排异反应的非侵入性技术的潜在发展和转化途径。

Summary Currently in clinical practice the detection of acute rejection usually depends on serum laboratory values such as serum creatinine or liver function tests, which tend to be insensitive and non-specific measures of organ injury. Ultimately the diagnosis of rejection requires needle biopsy of the transplanted organ. This invasive procedure is associated with increased cost and potential complications including injury to adjacent organs, bleeding and graft loss. In addition, graft biopsy is limited by sampling error where less than 0.01% of the allograft is examined, as well as inter-observer variability in the interpretation of the result. Patients often require multiple biopsies to assess response to treatment, thus putting them at risk each time they undergo a separate procedure. More recently, there has been significant effort in the development of non-invasive methods to detect rejection including gene expression profiling and -omic analysis of blood and urine samples. Despite recent high impact reports this strategy has not been widely adopted. Here we propose to develop and test non-invasive imaging techniques to monitor the allogeneic immune response to the transplanted organ. Specifically, we will utilize ImmunoPET to track and characterize T cell responses in the setting of CD28 costimulation blockade in vivo. We will use state of the art techniques in mouse models to investigate both naïve and memory T cell responses, where we will better define the mechanisms of costimulation blockade resistant rejection. Importantly, our preliminary data in mouse and NHP models reveal a critical role for CD122 in facilitating costimulation blockade-resistant responses; thus, we will use ImmunoPET to visualize the spatiotemporal patterns of CD122+ T cell accumulation following transplantation. We also propose to use ImmunoPET in our non-human primate kidney transplant model to gain further insight into the mechanisms of clinically relevant costimulation blockade-resistant rejection and assess clinical translatability. PET is already widely used in patients and techniques developed in this preclinical setting could be directly applied to clinical practice. This interdisciplinary application combines the expertise of two investigators: Dr. Santangelo who brings exceptional experience using state-of-the-art techniques to image the immune response such as ImmunoPET and Dr. Adams who brings clinical experience and an extensive understanding of novel anti- rejection therapies in transplantation, including costimulation blockade. The use of this powerful imaging technique combined with novel immunotherapies represents a highly innovative approach to further our understanding of the allogeneic immune response following transplantation. In addition, the ability to evaluate this technique not only in rodents but also in a preclinical non-human primate transplant model provides a clear path for potential development and translation of a non-invasive technique to predict rejection in patients.