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.

概括 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。 作为血清肌酐或肝功能测试，倾向于不敏感和非特异性器官测量 受伤。最终，对排斥反应的诊断需要对移植器官进行针头活检。这个侵入性 程序与成本增加和潜在并发症有关，包括对相邻器官的伤害， 出血和移植损失。此外，移植活检受到采样误差的限制，而该误差少于0.01％ 在结果解释中检查了同种异体移植物以及观察者间的变异性。病人经常 需要多个活检来评估对治疗的反应，从而使他们每次接受治疗的危险 单独的过程。最近，在非侵入性的发展方面付出了巨大的努力 检测排斥的方法，包括血液和尿液样品的基因表达分析和 - 摩西分析。 尽管有最近的高影响，但该战略尚未被广泛采用。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。 具体而言，我们将利用免疫物在CD28的设置中跟踪和表征T细胞响应 体内的共刺激封锁。我们将在鼠标模型中使用最先进的技术来研究这两者 天真和记忆T细胞响应，我们将更好地定义COLTIMUTUCTY BLOCKADE的机制 抗拒排斥。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 促进抗封闭封锁的反应；因此，我们将使用Immunopet可视化 移植后CD122+ T细胞积累的时空模式。我们还建议使用 在我们的非人类灵长类肾移植模型中免疫集，以进一步了解 临床上相关的共刺激避免阻滞性排斥反应和评估临床翻译性。宠物已经是 在这种临床前环境中开发的患者和技术广泛使用，可以直接应用于临床 实践。该跨学科应用程序结合了两个调查人员的专业知识：Santangelo博士谁 使用最先进的技术为免疫反应做出卓越的经验，例如 免疫网和亚当斯博士带来了临床经验，并对新的反 - 移植中的排斥疗法，包括共刺激阻塞。使用这种强大的成像 技术与新颖的免疫疗法相结合代表了一种高度创新的方法，可以进一步 了解移植后同种异体免疫反应。另外，评估能力 这种技术不仅在啮齿动物中，而且在临床前非人类灵长类动物移植模型中也提供了清晰的 潜在的发展和非侵入性技术转化的途径，以预测患者的排斥反应。