Multiparametric functional MRI for non-invasive assessment of acute and chronic renal transplant pathology in mice

尽管近来免疫抑制治疗有所改善，移植肾的长期存活率仍然有限。在移植后的早期阶段，由于缺血再灌注（IR）损伤，急性同种异体移植物排斥反应和延迟移植物功能的区分是至关重要的。移植肾晚期慢性排斥反应是导致移植肾功能衰竭的重要原因。然而，其机制在很大程度上是无法解释的，并且迄今为止尚未建立早期检测慢性移植物病理的非侵入性诊断方法。在以前的实验中，我们表明，功能性MRI允许在IR损伤后急性肾损伤的小鼠模型中进行肾脏病理学的非侵入性评估。因此，我们的项目的目的是，使用功能多参数MRI研究急性和慢性肾移植病理小鼠模型的肾脏病理。同时，通过与肾脏组织学、免疫组化和分子生物学检查的直接对比，验证功能MRI技术的有效性。第一部分，功能MRI技术在肾脏灌注评价中的应用（动脉自旋标记），组织水肿（T1-/T2-映射）、肾缺氧（BOLD）和细胞浸润，将优化肾纤维化和肾微观结构（扩散/扩散张量成像）以用于在小鼠模型中检查肾移植。第二部分将讨论急性肾移植病理学。功能性MRI技术将用于研究急性排斥反应（同种异体移植）和IR损伤（同基因移植）后的移植肾病理。MRI参数将直接与肾组织学和免疫组织化学（肾形态、细胞浸润、肾小管坏死、血管密度、ROS形成）、FACS分析和促炎细胞因子进行比较。第三部分将着重于研究慢性排斥反应（同种异体移植）后的慢性移植肾病理学和IR损伤诱导的移植物纤维化。与第二部分相似，MRI参数将与移植组织的分子和组织学变化相关，使用功能MRI对肾移植病理进行无创评估对于临床前研究和药物开发将是重要的，因为早期检测移植病理和在同一动物中进行纵向随访是可能的。此外，肾移植的功能性MRI可以提高肾移植后患者的诊断可能性。

Long term renal allograft survival remains limited despite recent improvements in immunosuppressive therapy. During the early phase after transplantation, differentiation between acute allograft rejection and delayed graft function due to ischemia reperfusion (IR) injury is crucial. At later stages, chronic renal allograft rejection is an important cause for allograft failure. However, the mechanisms are largely unexplained and non-invasive diagnostic methods to early detect chronic graft pathology have not been established so far. In previous experiments, we showed that functional MRI allows non-invasive assessment of renal pathology in a mouse model of acute kidney injury following IR injury. The purpose of our project is therefore, to use functional multiparametric MRI to investigate renal pathology in mouse models of acute and chronic renal graft pathology. Furthermore, the functional MRI techniques will be validated by direct comparison with renal histology, immunohistochemistry and molecular examinations.In the first part, functional MRI techniques for evaluation of renal perfusion (arterial spin labeling), tissue edema (T1-/T2-mapping), renal hypoxia (BOLD) and cellular infiltration, renal fibrosis and renal microstructure (diffusion/ diffusion tensor imaging) will be optimized for examination of kidney transplants in mouse models. The second part will address acute renal graft pathology. The functional MRI techniques will be used to investigate renal graft pathology after acute rejection (allogenic transplantation) and IR injury (isogenic transplantation). MRI parameters will be compared directly with renal histology and immunohistochemistry (renal morphology, cellular infiltration, tubular necrosis, vessel density, ROS formation), FACS analysis and proinflammatory cytokines. The third part will focus on examination of chronic renal allograft pathology following chronic rejection (allogenic transplantation) and IR injury induced graft fibrosis. Similar to the second part, MRI parameters will be correlated with molecular and histological changes of graft tissue.Non-invasive assessment of renal transplant pathology using functional MRI would be important for preclinical research and drug development, as early detection of graft pathology and longitudinal follow-up within the same animal is possible. In addition, functional MRI of renal transplants may improve diagnostic possibilities in patients after kidney transplantation.