Islet Transplantation

Drawing of a body torso showing the location of the liver and the pancreas with an enlargement of a pancreatic islet containing beta cells. Source: National Diabetes Information Clearinghouse (NDIC), National Institutes of Health.

Pancreatic islet transplantation is an experimental procedure in which insulin-producing beta cells are taken from a donor pancreas. The islets are purified, processed, and transferred into a recipient. Once implanted, the beta cells in these islets begin to make and release insulin. Researchers hope that islet transplantation will help people with Type 1 diabetes mellitus live without daily injections of insulin.

Description

The pancreas is an organ located behind the lower part of the stomach. Throughout the pancreas are clusters of cells called the islets of Langerhans. Islets are made up of several types of cells, including beta cells that make insulin.

Insulin is a hormone that helps the body use glucose for energy. Diabetes develops when the body does not make enough insulin, cannot use insulin properly, or both, causing glucose levels in the blood to increase. In type 1 diabetes (an autoimmune disease), the beta cells of the pancreas no longer make insulin because the body's immune system has attacked and destroyed them. A person who has type 1 diabetes must take insulin daily to live. Type 2 diabetes usually begins with a condition called insulin resistance, in which the body has difficulty using insulin effectively. Over time, insulin production declines as well, so many people with type 2 diabetes eventually need to take insulin.

Why Islet Transplantation Is Done

Current management of diabetes involves daily blood sugar testing, insulin injections, and careful meal planning. The only way to cure diabetes is to replace the destroyed beta cells or replace their function.

Whole-pancreas transplants have been successful in restoring insulin production in people with advanced diabetes, but because of significant risks the procedure has been limited to those who are also undergoing kidney transplantation.

For decades, researchers have searched for ways to restore blood sugar control through human islet transplantation, a procedure in which only the islets that contain insulin-producing beta cells are transplanted. In 2000, the Edmonton Protocol brought attention to a novel approach for islet transplantation. This transplantation method used a larger quantity of islets and a combination of drugs that was less toxic to suppress the immune system.

Islet transplantation is a simpler and less invasive procedure than whole-organ transplantation. Healthy islets are isolated from a donor pancreas, purified, and then infused through a small tube into the portal vein of the liver. Patients take immunosuppressive drugs to keep their bodies from rejecting the new islets. When successful, islet transplantation can restore normal blood sugar without the need for insulin injections and can improve quality of life.

Islet transplants are still experimental. Therefore, they are available only to people who participate in a clinical study and meet specific criteria in the study protocol. ^[1]

Preparation

The preparation for islet transplantation is relatively simple. The procedure is generally done using light sedation and takes a matter of hours. Recipients can often go home on the day of the procedure.

How Islet Transplantation Is Done

Drawing of two body torsos showing the infusion of islets extracted from a donor pancreas into a transplant recipient. Source: National Diabetes Information Clearinghouse (NDIC), National Institutes of Health.

Researchers use specialized enzymes to remove islets from the pancreas of a deceased donor. The islets are purified, processed, and transferred via catheter into the liver of the recipient through the portal vein. The new islets become embedded in the blood vessels of the liver and once implanted, the beta cells in these islets begin to make and release insulin. Because the islets are fragile, transplantation occurs soon after they are removed from the donor. Full function of the islets may not be immediate, so the patient's blood glucose will be monitored and insulin may still be required until the new islet cells become fully functional.

Typically a patient receives at least 10,000 islet equivalents”per kilogram of body weight, extracted from two donor pancreases. Patients often require two transplants to achieve insulin independence. Some transplants have used fewer islet equivalents taken from a single donated pancreas.

Transplants are often performed by a radiologist, who uses x rays and ultrasound to guide the catheter (small plastic tube) placement through the upper abdomen and into the portal vein of the liver. The islets are then infused slowly through the catheter into the liver. The patient receives a local anesthetic and a sedative. In some cases, a surgeon may perform the transplant through a small incision, using general anesthesia.

Benefits

The goal of islet transplantation is to infuse enough islets to control the blood glucose level without insulin injections. Other benefits may include improved glucose control and prevention of potentially dangerous episodes of hypoglycemia. Because good control of blood glucose can slow or prevent the progression of complications associated with diabetes, such as heart disease, kidney disease, and nerve or eye damage, a successful transplant may reduce the risk of these complications.

Risks

Complications

Rejection is the biggest problem with any transplant. The immune system is programmed to destroy bacteria, viruses, and tissue it recognizes as “foreign,” including transplanted islets. In addition, the autoimmune response that destroyed transplant recipients’ own islets in the first place can recur and attack the transplanted islets. Immunosuppressive drugs are needed to keep the transplanted islets functioning.

The Edmonton protocol introduced the use of a new combination of immunosuppressive drugs, also called anti-rejection drugs, including daclizumab (Zenapax), sirolimus (Rapamune), and tacrolimus (Prograf). Daclizumab is given intravenously right after the transplant and then discontinued. Sirolimus and tacrolimus, the two main drugs that keep the immune system from destroying the transplanted islets, must be taken for life or for as long as the islets continue to function. These drugs have significant side effects and their long-term effects are still not fully known. Immediate side effects of immunosuppressive drugs may include mouth sores and gastrointestinal problems, such as stomach upset and diarrhea. Patients may also have increased blood cholesterol levels, hypertension, anemia, fatigue, decreased white blood cell counts, decreased kidney function, and increased susceptibility to bacterial and viral infections. Taking immunosuppressive drugs also increases the risk of tumors and cancer.

Side Effects

Risks of islet transplantation include the risks associated with the transplant procedure—particularly bleeding and blood clots—and side effects from the immunosuppressive drugs that transplant recipients must take to stop the immune system from rejecting the transplanted islets.

Experts on Islet Transplantation

Funded by the National Institutes of Health and the Juvenile Diabetes Research Foundation, Human Islet Transplantation in Seattle (HITS} is one of nine sites testing the islet transplant procedure pioneered by Canada’s University of Alberta in Edmonton. The general focus of HITS is to improve ways to make islet transplantation an effective therapy for type 1 diabetes. Dr. R. Paul Robertson is the Program Director, and PNRI provides overall program direction. ^[2]

Researchers and institutions included in HITS are:

• Pacific Northwest Research Institute (PNRI)
• Virginia Mason’s Benaroya Research Institute
• Northwest Tissue Service
• University of Washington
• Puget Sound Blood Center
• Swedish Medical Center

Research

Recent news

• The use of donors who were previously excluded for weight, age or history death may provide a larger pool of qualified islet donors and allow for more patients to benefit from islet transplantation. ^[3]
• Recent developments in pancreas preservation are discussed. With improved methods of preservation, the donor pool may be increased and more patients may benefit from islet transplantation. ^[4]
• The use of a glucocorticid-free regimen of immunosupressant medicines appears to be an effective option to the traditional immunosupressant protocol for kidney and islet transplantation. ^[5]
• The financial issues concerning islet transplantation are discussed. ^[6]

New and emerging technologies

• Researchers continue to develop and study modifications to the Edmonton protocol drug regimen, including the use of new drugs and new combinations of drugs designed to help reduce destruction of transplanted islets and promote their successful implantation. These therapies may help transplant recipients achieve better function and durability of transplanted islets with fewer side effects. The ultimate goal is to achieve immune tolerance of the transplanted islets, where the patient’s immune system no longer recognizes the islets as foreign. If achieved, immune tolerance would allow patients to maintain transplanted islets without long-term immunosuppression.
• Researchers are also trying to find new approaches that will allow successful transplantation without the use of immunosuppressive drugs. For example, one study is testing the transplantation of islets that are encapsulated with a special coating designed to prevent rejection.
• A major obstacle to widespread use of islet transplantation is the shortage of islets. Although organs from about 7,000 deceased donors become available each year in the United States, fewer than half of the donated pancreases are suitable for whole organ pancreas transplantation or for harvesting of islets––enough for only a small percentage of those with type 1 diabetes. However, researchers are pursuing various approaches to solve this problem, such as transplanting islets from a single donated pancreas, from a portion of the pancreas of a living donor, or from pigs. Researchers have transplanted pig islets into other animals, including monkeys, by encapsulating the islets or by using drugs to prevent rejection. Another approach is creating islets from other types of cells, such as stem cells. New technologies could then be employed to grow islets in the laboratory.

Clinical Trials

A list of ongoing clinical trials is available here: islet transplantation trials

References

1. ↑ U.S. Food and Drug Administration web site. Pancreatic Islet Transplantation to Treat Type I Diabetes. General Information - September 10, 2003.
2. ↑ Human Islet Transplantation in Seattle (HITS) web site. Human Islet Transplantation in Seattle (HITS)
3. ↑ Neidlinger NA, Odorico JS, Sollinger HW, Fernandez LA. Can 'extreme' pancreas donors expand the donor pool? Curr Opin Organ Transplant. 2008 Feb;13(1):67-71. Abstract
4. ↑ Baertschiger RM, Berney T, Morel P. Organ preservation in pancreas and islet transplantation. Curr Opin Organ Transplant. 2008 Feb;13(1):59-66. Abstract
5. ↑ Tan J, Yang S, Cai J. Simultaneous Islet-Kidney Transplantation in 7 Patients of Type 1 Diabetes with End-stage Renal Disease using a glucocorticoid-free immunosuppressive regimen with alemtuzumab induction. Diabetes. 2008 Jul 15. (Epub ahead of print) [http:/pubmed.gov/18633105 Abstract]
6. ↑ Markmann JF, Kaufman DB, Ricordi C, Schwab PM, Stock PG. Financial Issues Constraining the Use of Pancreata Recovered for Islet Transplantation: A White Paper. Am J Transplant. 2008 Jun 12. (Epub ahead of print) Abstract

External Links

American Diabetes Association

International Pancreas and Islet Transplant Association

Clinical Islet Transplantation Consortium