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

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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).