Pre-clinical in vivo imaging of islet transplantation in non-human primates

描述（由申请人提供）：1型糖尿病（T1 D）由免疫介导的胰腺β细胞破坏引起，这导致胰岛素分泌不足，并因此导致高血糖症。由于胰岛移植成为一种可接受的临床模式，用于恢复正常的T1 D患者，有一个非侵入性评估移植移植物的命运的迫切需要。尽管埃德蒙顿方案取得了成功，但由于移植后立即发生的免疫和非免疫事件，发生了显著的移植物损失。因此，使用可靠的非侵入性方法监测胰岛排斥反应将显著有助于移植成功的临床评估。我们以前已经开发了一种方法来非侵入性地检测人类胰岛标记的磁共振造影剂和移植下的肾包膜在小鼠使用磁共振成像（MRI）。此外，我们建立了一种方法来检测标记的人胰岛移植（肝内输注）的临床前模型，并表明胰岛排斥反应可以监测非侵入性和重复在真实的时间通过MRI。此外，在本研究中，我们采用了FDA批准的市售造影剂（Feridex）标记胰岛细胞，该造影剂在临床上用于肝脏成像。该试剂与我们的胰岛移植临床前模型的结合将促进成像免疫排斥反应向临床试验的过渡。然而，在将该方法过渡到临床试验之前，有必要在非人灵长类动物中对其进行验证。我们建议使用人类临床成像设备和人类使用可行的成像序列。此外，对于在大型动物中开发的胰岛移植的新实验模型的结果的非侵入性评估存在巨大的需求，其中成本过高并且杀死动物不可行。在治疗上，这项技术将有助于确定何时需要额外的免疫抑制治疗。在诊断上，它将产生关于移植胰岛命运的数据，而无需多次活检损害移植物。因此，在我们的具体目标中，我们将1）验证胰岛移植体内成像在非人灵长类动物肝内输注临床前模型中的应用，2）研究非人灵长类动物胰岛移植实验模型（胰岛-肾复合移植模型）中胰岛移植物的体内成像。

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) results from immune mediated destruction of pancreatic beta-cells, which leads to a deficiency in insulin secretion and as a result, to hyperglycemia. As islet transplantation becomes an acceptable clinical modality for restoring normoglycemia in T1D patients, there is a critical need for non-invasive assessment of the fate of the transplanted grafts. In spite of the success of the Edmonton protocol, a significant graft loss occurs due to immunological as well as non-immunological events immediately after transplantation. Therefore, monitoring of islet rejection using reliable non-invasive methods would significantly aid in the clinical assessment of graft success. We have previously developed a method to non-invasively detect human islets labeled with an MR contrast agent and transplanted under the kidney capsule in mice using magnetic resonance imaging (MRI). Furthermore, we established a method to detect labeled human islets in a pre-clinical model of human islet transplantation (intrahepatic infusion) and showed that islet rejection could be monitored non-invasively and repeatedly in real time by MRI. In addition, in this study we have adapted for islet cell labeling an FDA-approved commercially available contrast agent (Feridex) that is used clinically for liver imaging. The combination of this agent with our pre-clinical model of islet transplantation will facilitate the transition of imaging immune rejection to clinical trials. However, before transition of this method into clinical trials, it is necessary to validate it in non-human primates. We propose to use human clinical imaging equipment and imaging sequences that are feasible for human use. In addition, there is an enormous need for non-invasive evaluation of the outcome of new experimental models of islet transplantation that are being developed in large animals, where the cost is prohibitive and killing animals is not feasible. Therapeutically, this technique will aid in determining when additional immunosuppressive therapy is needed. Diagnostically, it will produce data on the fate of the transplanted islets without multiple biopsies damaging the grafts. Therefore, in our Specific Aims we will 1) Validate the application of in vivo imaging of islet transplantation in pre-clinical model of intrahepatic infusion in non-human primates and 2) Investigate the in vivo imaging of islet grafts in experimental model of islet transplantation in non-human primates (islet-kidney composite transplant model).