Imaging Costimulation Blockade Resistant Rejection

成像共刺激封锁抗拒绝

• 批准号: 10378791
• 负责人: Andrew B Adams
• 金额: $ 46.06万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378791
• 关键词: Imaging; Costimulation; Blockade; Resistant; Rejection

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.

总结 目前在临床实践中，急性排斥反应的检测通常取决于血清实验室值， 如血清肌酐或肝功能检查，这些检查往往是对器官不敏感和非特异性的测量， 损伤排斥反应的诊断最终需要对移植器官进行穿刺活检。这种侵入性 手术与成本增加和潜在并发症（包括邻近器官损伤）有关， 出血和移植物丢失。此外，移植物活检受到采样误差的限制，其中小于0.01%的 检查同种异体移植物，以及结果解释中的观察者间差异。患者往往 需要多次活检来评估对治疗的反应，从而使他们在每次接受 单独的程序。最近，在开发非侵入性的生物传感器方面已经做出了重大努力。 检测排斥的方法包括基因表达谱分析和血液和尿液样品的组学分析。 尽管最近的报告影响很大，但这一战略尚未得到广泛采用。在这里，我们建议发展和 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。 具体来说，我们将利用ImmunoPET来跟踪和表征T细胞反应的CD 28的设置， 体内共刺激阻断。我们将在小鼠模型中使用最先进的技术来研究这两种情况。 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 抗排斥反应重要的是，我们在小鼠和NHP模型中的初步数据揭示了CD 122的关键作用。 促进共刺激阻断抵抗反应;因此，我们将使用ImmunoPET来可视化 移植后CD 122 + T细胞积累的时空模式。我们还建议使用 免疫PET在我们的非人灵长类动物肾移植模型中的应用，以进一步了解 临床相关的共刺激阻断抵抗性排斥反应，并评估临床可翻译性。PET已经 广泛用于患者，并且在该临床前环境中开发的技术可以直接应用于临床 实践这种跨学科的应用结合了两位研究人员的专业知识：Santangelo博士， 使用最先进的技术来成像免疫反应，如 免疫PET和亚当斯博士谁带来的临床经验和广泛的了解，新的抗- 移植中的排斥治疗，包括共刺激阻断。使用这种强大的成像技术 技术结合新的免疫疗法代表了一种高度创新的方法，以进一步我们 了解移植后的同种异体免疫反应。此外，评估能力 该技术不仅在啮齿类动物中，而且在临床前非人灵长类动物移植模型中提供了明确的 一种预测患者排斥反应的非侵入性技术的潜在开发和转化途径。