Magnetic resonance imaging (MRI) with an approved contrast agent may provide a practical way of monitoring the survival of transplanted pancreatic islets. In the September issue of the journal Diabetes, researchers from the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH) report successfully tracking over time the fate of islets transplanted into mice using a protocol currently being tested in human patients.
"Clinical trials and animal studies show that there is a significant loss of islets following transplantation due to many factors, not just rejection," says Anna Moore, PhD, of the MGH Martinos Center, who led the study. "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."
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, since it was developed at the University of Alberta - 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 post-transplantation engraftment of islets. Even in animal studies involving transplants from genetically identical donors, which should not produce immune rejection, as many as 60 percent of islets are lost in 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 current study utilized islets labeled with Feridex, an FDA-approved contrast agent, and procedures virtually identical to the Edmonton protocol, in which islets are infused into the recipient's liver. Labeled islets were transplanted into mice with a normal immune system and into mice with a severe genetic immune deficiency that would practically eliminate the rejection process. MR images of the animals' livers were taken seven times over the 14 days after the transplant procedure.
The results verified that 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 percent greater loss of islets than did the immune-deficient animals - probably the result of rejection - and 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," says Moore. "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." Moore is an assistant professor of Radiology at Harvard Medical School and director of the Molecular Imaging Laboratory at the Martinos Center.
Co-authors of the Diabetes report are first author Natalia Evgenov, MD, Zdravka Medarova, PhD, John Pratt, PhD, Pamela Pantazopoulos, and Simone Leyting of the Martinos Center at MGH, and Susan Bonner-Weir, PhD, Joslin Diabetes Center. The research was supported by grants from the National Institutes of Health.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
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