NONINVASIVE DETECTION OF ORGAN REJECTION BY MRI

这项研究计划的目标是开发一种非侵入性的 检测实体器官中急性移植物排斥反应早期体征的方法 移植，特别是通过核磁共振（NMR） 磁共振成像（MRI）和磁共振成像（MRI）技术 共振波谱（MRS）。为了实现我们的目标，我们 组建了一个跨学科的团队，由三个互动的 实验室：（I）Chien Ho，Ph.D.卡内基梅隆大学， 生物化学-生物药理学家，以及应用MRI和MRS技术的专家 生物医学问题;（ii）Suzanne T. lldstad，医学博士大学的 匹兹堡，外科医生，免疫学家，移植专家 耐受性、干细胞生物学和异种移植;和（iii）Pedro J. del Nido，医学博士哈佛医学院儿童医院 波士顿，心脏外科医生和儿科心脏外科专家，心脏 移植和器官排斥。 这三位研究人员 互补的专业知识，进行了合作研究期间， 在过去的三年里，并发表了联合科学论文。 尽管 免疫抑制治疗在移植物免疫控制中的重要进展 排斥反应，排斥反应的诊断仍然是最困难的方面， 移植病人的管理。 组织活检通常 被认为是诊断移植排斥反应的“金标准”。 的 使用组织活检来监测移植排斥不仅是侵入性的， 但也有其他的局限性和复杂性。 急性期早期 排斥，细胞侵入过程通常是局部的，影响免疫应答。 器官的离散区域。 早期排斥反应的病灶性质 过程增加了在执行 组织活检 通常需要多次活检，从而增加了 并发症的风险，特别是在儿科患者中。 我们的工作 假设是，如果我们能开发出一种非侵入性的方法来跟踪 T细胞向移植排斥部位的运动，我们将有一个非- 侵入性技术来检测器官排斥的早期迹象。 我们有 选用大鼠模型作为实验系统。 我们的具体目标 建议的研究将包括以下项目：（一）优化 用合适的MRI造影剂标记分离的T细胞，（ii） 改善氧化铁标记的T细胞的MRI检测;（iii）开发 追踪用各种MRI标记的T细胞所需的MRI技术 心脏和肾移植中的造影剂;（iv）确定 急性排斥反应的早期体征，通过比较MRI结果（获得 从跟踪T细胞运动和器官灌注研究）与那些从 31 P-MRS和常规组织学检查结果;（v）研究 对大鼠移植模型的免疫抑制作用， 这些发现与MRI、MRS和组织学结果相结合。 如果我们的提议 方法是成功的，我们对发展我们的方法寄予厚望。 作为一种非侵入性的诊断工具，用于检测急性 人体器官移植的排斥反应。 因此，一个可靠的，非- 侵入性诊断技术检测移植物排斥反应早期体征 将使医生有更多的时间给予适当的 免疫抑制剂治疗以预防和控制移植物排斥。

The goal of this proposed research project is to develop a non-invasive method to detect early signs of acute graft rejection in solid-organ transplantation, specifically by nuclear magnetic resonance (NMR) techniques, such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). In order to achieve our goal, we have assembled an interdisciplinary team consisting of three interactive laboratories: (I) Chien Ho, Ph.D. of Carnegie Mellon University, a biochemist-biophysicist, and an expert in applying MRI and MRS techniques to biomedical problems; (ii) Suzanne T. lldstad, M.D. of the University of Pittsburgh, a surgeon, an immunologist, and an expert in transplantation tolerance, stem cell biology, and xenotransplantation; and (iii) Pedro J. del Nido, M.D. of Harvard Medical School and Children's Hospital of Boston, a cardiac surgeon and an expert in pediatric heart surgery, heart transplantation, and organ rejection. These three researchers have complementary expertise, have carried out collaborative research during the past three years, and have published joint scientific papers. Despite significant advances in immunosuppressive therapy for the control of graft rejection, the diagnosis of rejection remains the most difficult aspect in the management of transplant patients. Tissue biopsy is generally accepted as the "gold standard" in the diagnosis of graft rejection. The use of tissue biopsies to monitor graft rejection is not only invasive, but also has other limitations and complications. Early in acute rejection, the cellular invasion process is commonly focal, affecting a discrete area of the organ. The focal nature of the early rejection process increases the likelihood of sampling error when performing a tissue biopsy. Multiple biopsies are often required, thus increasing the risk of complications, especially in pediatric patients. Our working hypothesis is that if we can develop a non-invasive method to track the movement of T-cells to the site of graft rejection, we will have a non- invasive technique to detect the early signs of organ rejection. We have chosen the rat model as our experimental system. The specific aims of our proposed research will include the following projects: (I) to optimize the labeling of isolated T-cells with suitable MRI contrast agents, (ii) to improve the MRI detection of iron-oxide labeled T-cells; (iii) to develop MRI techniques needed for tracking T-cells labeled with various MRI contrast agents in cardiac and renal transplantations; (iv) to determine the early signs of acute rejection by comparing the MRI results (obtained from tracking T-cell movement and organ perfusion studies) with those from 31P-MRS and the conventional histological findings; and (v) to investigate immunosuppressant effects on the rat transplant model and to correlate these findings with MRI, MRS, and histological results. If our proposed approach is successful, we have high hopes of developing our methodology as a non-invasive diagnostic tool for detecting early signs of acute rejection in organ transplantation in humans. Thus, a reliable, non- invasive diagnostic technique to detect early signs of graft rejection will allow physicians more time to administer appropriate immunosuppressants therapy to prevent and to control graft rejection.