DEVELOPMENT OF MRI TO DETECT CARDIAC REJECTION

描述（由申请人提供）： 拟议研究的最终目标是使用非侵入性成像方法，通过改善急性和慢性移植物功能障碍的检测和治疗来改善移植患者的管理。近期的目标是使用大鼠同种异体移植模型，开发无创的细胞和功能磁共振成像（MRI）的方法来监测免疫细胞浸润到移植心脏和监测移植心脏的功能，从而发现心脏移植后的移植心肌排斥反应（AMR）和心脏移植血管病变（CAV）的早期迹象。当器官排斥发生时，免疫细胞在排斥心脏处积聚。MRI造影剂，例如，葡聚糖包被的超小超顺磁性氧化铁（USPIO）颗粒和其它颗粒可以通过吞噬作用/内吞作用掺入大鼠巨噬细胞和/或T细胞中。这些颗粒或标记的细胞可以静脉内引入，以监测移植物排斥部位的免疫细胞积累。我们提出的研究的具体目标是：（i）改进现有的和开发新的细胞标记技术，将合适的MRI造影剂纳入免疫细胞;（ii）改进现有的和开发新的细胞和功能性MRI技术，用于检测体内急性和慢性心脏排斥反应;（iii）通过MRI监测免疫细胞在体内排斥心脏处的积累，作为新的非免疫细胞聚集。有创性方法检测急性和慢性排斥反应，并监测移植心脏在急性和慢性排斥反应不同阶段的功能变化，我们的异位工作心脏大鼠模型，有和没有治疗干预;和（iv）相关的结果来自细胞和功能性MRI测量移植心脏与传统的组织病理学，免疫学和生化参数，以评估心脏排斥反应，以验证我们的方法和相关的MRI标记的免疫细胞浸润与心肌功能。所提出的心脏MRI技术本质上是通用的，并且可以应用于监测患有其他心脏疾病的患者，例如，炎性心肌病通过允许在基线和治疗干预下对受损组织进行成像，细胞和功能MRI为临床医学提供了巨大的潜力。MRI跟踪细胞迁移可用于监测研究和临床目的的任何类型细胞的运输。

DESCRIPTION (provided by applicant): The ultimate goal of the proposed research is to use non-invasive imaging methodology to improve the management of transplant patients by improving the detection and treatment of acute and chronic allograft dysfunction. The immediate objective is to use rat allograft models to develop non-invasive methods of cellular and functional magnetic resonance imaging (MRI) to monitor the infiltration of immune cells into the transplanted heart and to monitor the function of transplanted hearts, and thereby to detect early signs of allograft myocardial rejection (AMR) and cardiac allograft vasculopathy (CAV) following heart transplantation. When organ rejection occurs, immune cells accumulate at the rejecting heart. MRI contrast agents, e.g., dextran-coated ultra small superparamagnetic iron-oxide (USPIO) particles and others can be incorporated into rat macrophages and/or T-cells by phagocytosis/endocytosis. These particles or labeled cells can be introduced intravenously to monitor the accumulation of immune cells at the site of graft rejection. The specific aims of our proposed research are: (i) to improve existing and to develop new cell labeling techniques to incorporate suitable MRI contrast agents into immune cells; (ii) to improve existing and to develop new cellular and functional MRI techniques for detecting acute and chronic cardiac rejection in vivo; (iii) to monitor by MRI the accumulation of immune cells at the rejecting heart in vivo as a new non-invasive approach to detect acute and chronic rejection and to monitor functional changes of the transplanted heart during various stages of acute and chronic rejection in vivo in our heterotopic working heart rat models with and without therapeutic intervention; and (iv) to correlate the results derived from cellular and functional MRI measurements of transplanted hearts with conventional histopathological, immunological, and biochemical parameters for evaluating cardiac rejection in order to validate our methods and to correlate infiltration of MRI-labeled immune cells with myocardial function. The proposed cardiac MRI techniques are general in nature 'and can be applied to monitor patients with other cardiac disorders, e.g., inflammatory cardiomyopathies. By allowing imaging of injured tissues at baseline and with therapeutic intervention, cellular and functional MRI offers great potential for clinical medicine. MRI tracking of cell migration can be applied to monitor the trafficking of any type of cells for research and clinical purposes.