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（T1D）是由免疫介导的胰腺β细胞破坏引起的，这导致胰岛素分泌不足，从而导致高血糖。随着胰岛移植成为T1D患者恢复正常血糖的一种可接受的临床方式，迫切需要对移植移植物的命运进行无创评估。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，严重的移植物损失发生。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。我们之前已经开发了一种无创检测方法，使用磁共振成像（MRI）在小鼠肾包膜下移植用磁共振造影剂标记的人类胰岛。此外，我们建立了一种在人类胰岛移植（肝内输注）临床前模型中检测标记人类胰岛的方法，并表明通过MRI可以无创地实时重复监测胰岛排斥反应。此外，在这项研究中，我们采用了fda批准的市售造影剂（Feridex）用于胰岛细胞标记，该造影剂在临床上用于肝脏成像。这种药物与我们的临床前胰岛移植模型的结合将促进影像学免疫排斥向临床试验的过渡。然而，在将该方法过渡到临床试验之前，有必要在非人类灵长类动物中进行验证。我们建议使用适合人类使用的人类临床成像设备和成像序列。此外，对正在大型动物身上开发的新的胰岛移植实验模型的结果进行无创评估是非常必要的，因为这些模型的成本高昂，而且杀死动物是不可行的。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)验证胰岛移植的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)研究胰岛移植在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).