Islet Cell Transplants Reviewed

Researchers from 12 medical centers in the United States and Canada, who have performed islet transplants in 86 patients with type 1 diabetes, published their results in the first annual report of the Collaborative Islet Transplant Registry (CITR). The report (www.citregistry.org ) analyzes many factors that can affect the outcome of this experimental procedure for people with severe or complicated type 1 diabetes.

The report provides data on recipient and donor characteristics, pancreas procurement and islet processing, immunosuppressive medications, function of the donated islets, patients' lab results, and adverse events. "We now have much-needed information on the short-term results of islet transplantation," said Dr. Thomas Eggerman of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "Our goal is to collect data on both short- and long-term outcomes for all patients who receive islet transplants so we can better define the overall risks and benefits of this exciting but still experimental procedure."

Type 1 diabetes, which affects up to 1 million people in the United States, develops when the body's immune system destroys the insulin-producing beta cells of the pancreas. This form of diabetes usually strikes children and young adults, who need several insulin injections a day or an insulin pump to survive. Insulin, however, is not a cure, and eventually most people with type 1 diabetes develop one or more complications of the disease, including damage to the heart and blood vessels, eyes, nerves, and kidneys.

In islet transplantation as performed by these centers, insulin-producing cells derived from donor pancreata were infused into patients with difficult-to-control type 1 diabetes though the portal vein of the liver. When successful, the transplanted islets took up residence in the liver's small blood vessels and began producing insulin.

The 86 recipients, who had type 1 diabetes for an average of 30 years, received a total of 158 infusions of islets extracted from 173 donor pancreata. Twenty-eight patients received one islet infusion, 44 received two, and 14 received three. At 6 months after the last infusion, 61% of recipients no longer had to inject insulin. At 1 year after the last transfusion, 58% were still insulin independent. Some insulin-independent patients, although not receiving insulin, did have higher-than-normal blood glucose levels. Researchers will continue to monitor patients to see how long they remain insulin independent.

Recipients, 66% of whom were women, were an average age of 42 years (range 24 to 64 years) and average weight of 143 lbs. (range 103 to 213 lbs.). Before the procedure, nearly half the recipients were using an insulin pump. Most had recently experienced at least one episode of hypoglycemia, or dangerously low blood glucose, requiring another person's help. Their average level of hemoglobin A1c (HbA1c), which reflects blood glucose control over the previous 3 months, was 7.7%, compared to a normal HbA1c of 6%.

HbA1c levels generally improved with each infusion, as did levels of fasting blood glucose and C-peptide, which reflect insulin production. One infusion, though rarely providing enough islets to free a person from the need to inject insulin, alleviated episodes of severely low blood glucose. After the first infusion of islets, only two recipients had a low blood sugar problem requiring the help of another person. None of those who received a single infusion reported a problem with hypoglycemia a year after the procedure.

"Data collection on islet transplantation has been difficult, because most of the 750 islet transplants performed worldwide since 1974 have been done as part of small, single-center pilot trials," said Dr. Bernhard Hering of the University of Minnesota, who chairs CITR's scientific advisory committee. "This report is an important collaborative effort to combine data from 12 centers on the risks and successes of islet transplantation and to make the information widely available to patients and investigators."

From 1990 to 1999, only 8% of islet transplants resulted in insulin independence for more than 1 year. In 2000, however, a group of researchers led by Dr. James Shapiro at the University of Alberta in Edmonton, Canada, reported much greater success in patients transplanted with islets from two to four donor pancreata and treated with an immunosuppressive regimen that left out glucocorticoids, now thought to be toxic to islets. In the next few years, other researchers replicated the "Edmonton protocol" pioneered by the Canadian team, and many centers are now using this approach to islet transplantation.

The centers reported 45 serious adverse events but no deaths in the recipients. The 27% of events that were classified as life-threatening included those linked to the transplant procedure itself (e.g., infection, bleeding into the chest or abdomen, low hemoglobin, high liver enzymes) and to medications that suppress the immune system (e.g., anemia, nerve damage, meningitis, and low numbers of white blood cells). Most recipients received the same drug regimen used in the Edmonton protocol: daclizumab at induction to prevent the immune system from rejecting the donor islets and sirolimus combined with tacrolimus to maintain immunosuppression.

The CITR's mission is to expedite progress and promote safety in islet transplantation by collecting analyzing, and communicating data on islet transplantation. NIDDK established the registry in 2001 through a contract awarded to EMMES Corporation in Rockville, Maryland.

In the CITR's first report, 12 islet transplant centers detail the experiences of 86 patients who received at least one islet transplant from 1999 to 2003. Omitted from the report are outcomes for 74 other recipients at these centers and data on about 40 people who received islet transplants in other centers during this time. "We're continuing to receive additional data from the inaugural 12 centers and from new centers joining and contributing data, so future reports will be even more comprehensive," noted Dr. Eggerman.

"The CITR will prove invaluable, not only to investigators, but to all parties with an interest in moving the field forward," added Dr. Brian Flanagan, Scientific Program Manager at the Juvenile Diabetes Research Foundation International (JDRF). Recently, five islet transplant centers in Europe, with JDRF funding, began contributing data to the CITR.

"In addition to collecting data on islet transplant outcomes, the CITR is integrating data from other sources, such as the United Network for Organ Sharing (UNOS) and the Islet Cell Resource Centers. This effort will give us critical information on donor characteristics, organ procurement, islet processing, and other key variables that influence the success of islet transplantation," said Dr. Camillo Ricordi of the Diabetes Research Institute at the University of Miami, who serves on the CITR's scientific advisory committee.

The CITR is supported by a special funding program for type 1 diabetes research, which provides a total of $1.14 billion from fiscal year 1998 through fiscal year 2008 to supplement other funds for type 1 diabetes research made available through the regular NIH appropriations process.

Because only about 6,000 donor pancreata become available each year, and many are used for whole organ transplantation, the scarcity of islets poses a major obstacle to wider testing of islet transplantation as a treatment for type 1 diabetes. To improve the potential of cell replacement therapy for type 1 diabetes, NIH-funded research is focusing on understanding the beta cell and its regeneration and on efforts to develop alternative sources of beta cells. Researchers are also working on ways to coax the immune system into accepting donated cells or tissues without suppressing the whole immune system.