MR contrast tracks transplanted pancreatic islets

September 13, 2006

By the time Feridex was ready for the U.S. market in 1996, CT had already established itself as the tool of choice in the liver. That relegated the first organ-specific MR contrast agent to a decade of underutilization. But research conducted at Massachusetts General Hospital indicates that the superparamagnetic iron oxide agent may be a practical way to monitor survival of transplanted pancreatic islets in patients with type 1 diabetes.

By the time Feridex was ready for the U.S. market in 1996, CT had already established itself as the tool of choice in the liver. That relegated the first organ-specific MR contrast agent to a decade of underutilization. But research conducted at Massachusetts General Hospital indicates that the superparamagnetic iron oxide agent may be a practical way to monitor survival of transplanted pancreatic islets in patients with type 1 diabetes.

In a preclinical study reported in the September issue of Diabetes, researchers from the MGH Martinos Center for Biomedical Imaging used MRI to track the fate of islets transplanted into mice. The preclinical transplantation protocol is the same as one now undergoing testing in human patients with type 1 diabetes.

"Clinical trials and animal studies show that there is a significant loss of islets following transplantation due to many factors, not just rejection," said research leader Anna Moore, Ph.D., an assistant professor of radiology at Harvard Medical School and director of the Molecular Imaging Laboratory at the Martinos Center. "Currently there is no direct way to follow the causes behind this loss and how it proceeds over time. Monitoring islet survival by noninvasive imaging could give us the ability to detect and measure rates of islet loss under a variety of conditions, which could help develop procedures leading to better therapeutic outcomes."

The last time anyone considered an extension of the agent's clinical reach was five years ago, when its developer, Advanced Magnetics, submitted a supplemental new drug application to the FDA for the differentiation of liver lesions as benign or metastatic. The effort ended badly, when the FDA declared the application "not approvable." This latest opportunity may have a better chance of working out.

Pancreatic islet transplants are being investigated as a way to treat or cure patients with type 1 diabetes, in which the insulin-producing islets are attacked by the body's immune system. In an effort to replace destroyed islets and restore normal insulin production and glucose metabolism, several methods of islet transplantation have been developed and tested. One of the most promising - called the Edmonton Protocol, named for the University of Alberta, where it was developed - is currently the subject of a multicenter clinical trial.

In a 2005 report, the Edmonton group noted that, while islet survival is improving, problems continue to exist both with immune rejection and with the initial posttransplantation grafting of islets. Even in animal studies involving transplants from genetically identical donors, which should not produce immune rejection, as many as 60% of islets are lost soon after the procedure.

In a previously published animal study, the MGH Martinos group showed that MRI could detect transplanted islets that had been marked with experimental iron-containing nanoparticles. The newly published study used islets labeled with Feridex and procedures similar to the Edmonton protocol, in which islets are infused into the recipient's liver.

Labeled islets were transplanted into mice with normal immune systems as well as mice with severe genetic immune deficiencies that would practically eliminate the rejection process. MR images of the animals' livers were taken seven times over the 14 days following the transplant procedure.

The results verified that MRI could track the labeled islets over time and reveal how many were surviving. For both groups of mice, the number of islets began to drop immediately after transplantation and reached a plateau at 10 to 14 days. The researchers note that much of the early islet death probably was caused by factors other than rejection, such as damage during the transplant procedure. However, by day 10 the mice with normal immune systems showed a 20% greater loss of islets than did the immune-deficient animals, probably the result of rejection. Close examination verified significant immune cell activity in the normal mice.

"Since MRI can provide comprehensive information about the presence and position within the body of entities as small as islets and can be performed repeatedly without subjecting patients to radiation or any invasive procedure, we think it is the most appropriate imaging modality to monitor islet survival," Moore said. "Feridex is an approved imaging agent, so the next logical step could be human clinical trials, although it may be helpful to work on improving the imaging procedures with larger animals first."