Islet Transplantation Pancreatic Islet Transplantation Advancements in

Islet Transplantation

Pancreatic Islet Transplantation

Advancements in the areas of beta cell replacement and islet transplantation are slow in coming and the latest long-term success rates are disappointing, as less than 14% of transplant recipients remain free of insulin therapy after two years (Mayo, p. 1).

In type 1 diabetes, the body destroys its own insulin producing cells. The body's immune system attacks and destroys cells in the pancreas called beta cells. These cells are contained within small islands of endocrine cells called pancreatic islets.

In 1993 the Diabetes Control and Complications Trial (DCCT) established the modern standard of care for the medical management of type 1 diabetes mellitus. The DCCT assigned 1441 patients to intensive or conventional treatment. The first step included daily determinations of blood glucose levels several times daily at home by finger stick; then daily injections of long-, intermediate-, and short-acting insulin; accompanied by dietary and psychological support (Robertson, p. 694).

Diabetic complications may include hypoglycemia, diabetic hyperosmolar syndrome, diabetic ketoacidosis, neuropathy, nephropathy, retinopathy, heart and blood vessel disease, and increased risk of infection. Controlling the disease is difficult. Monitoring blood glucose, eating a healthy diet, getting daily exercise, and maintaining a healthy weight are part of maintenance. Medical therapies for managing diabetes include the use of insulin to manage type 1 and type 2 diabetes and the use of sulfonylureas, meglinitides, biguanides, alpha glucosidase inhibitors, thiazolidinediones, and drug combinations to manage type 2 diabetes (Collazo-Clavel, p. 5).

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.

Healthy islets are isolated from a donor pancreas, purified, and then infused through a small tube into the portal vein of the liver. Patients must 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, so they are available only to people who participate in a clinical study and meet specific criteria (U.S., p. 1).

Replacing these cells via transplantation has been the subject of research for many years. Transplantation of beta cell containing islets is less invasive than transplanting a whole pancreas, which was the established procedure before 1993. In a procedure called islet transplantation, islets are transferred into a faulty pancreas from a healthy donor pancreas. The beta cells in these islets begin to make and release insulin, once implanted. Researchers hope that islet transplantation will help people with type 1 diabetes live without daily injections of insulin. (Pancreatic, p. 1)

The Islets of Langerhans

The pancreas makes enzymes and insulin that help digest and use food. Spread over the pancreas are clusters of cells called the islets of Langerhans. Islets are made up of two types of cells: alpha cells, which make glucagon, a hormone that raises the level of glucose (sugar) in the blood, and beta cells, which make insulin. Insulin, a hormone, helps the body use glucose for energy. If beta cells do not make enough insulin, diabetes develops. In type 1 diabetes, an autoimmune process causes insulin shortage by the body's immune system destroying the beta cells.

Having reported their findings in the June 2000 issue of the New England Journal of Medicine, researchers at the University of Alberta in Edmonton, Canada, continue to use the Edmonton protocol to transplant pancreatic islets into people with type 1 diabetes. In 2000, a multi-center clinical trial of the Edmonton protocol for islet transplantation took place, and the promising results were announced. According to the Immune Tolerance Network (ITN), in June 2003, about 50% of the patients remained insulin-free up to 1-year after receiving a transplant. A clinical trial of the Edmonton protocol also was conducted by the ITN, funded by the National Institutes of Health and the Juvenile Diabetes Research Foundation International. (Pancreatic, p. 1).

This year (2006), further trials on an international scale were reported in the New England Journal of Medicine. Believing that islet transplantation offers the best potential to improve glycemic control in type 1 diabetics, an international, multicenter trial to explore the feasibility and reproducibility of islant transplantation was done with the use of a single common protocol, the Edmonton protocol. 36 subjects with type 1 diatetes mellitus underwent islent transplantation at nine international sites. Islets from the pancreases of deceased donors were transplanted within 2 hours after purification, without culture. The goal was defined to be insulin independence with adequate glycemic control after one year following the final transplantation.

Of the 36 subjects, 44% met the goal, 28% had partial function and 28% had complete graft loss. The 21 subjects who attained insulin independence had good glycemic control throughout the trial. 76% of these, however, required insulin again at two years, while 31% remained insulin-free at two years (Shapiro, p. 1330).

In this procedure, researchers use specialized enzymes to remove islets from the pancreas of a deceased donor. Because the islets are fragile, transplantation occurs very soon after they are removed from the deceased donor. (Pancreatic, p. 1)

Ultrasound is used by the surgeon during the transplant to guide placement of a small plastic tube (catheter) through the upper abdomen into the liver. The islets are injected through the catheter into the liver. The patient may receive a local anesthetic or general anesthesia while the surgeon does the transplant through a small incision. Risks include bleeding or blood clots.

It takes awhile for cells to attach to new blood vessels in the recipient patient, to begin releasing insulin. The doctor orders tests to check blood glucose levels after the transplant, and insulin may be needed until control is achieved.(Ibid.)

Transplantation: Benefits, Risks, and Obstacles

Islet isolation and purification, transplantation, and other new strategies toward tolerance induction have been researched in recent years. Islet cell transplantation can be performed as a percutaneous minimally invasive procedure. Islets are infused into the liver via the portal vein. This transplantation modality could circumvent the organ shortage that prevents most patients with diabetes who are eligible from pancreas transplantation from actually receiving a graft. The graft offers the possibility of maintaining a healthy pancreas without chronic immunosuppressive drugs when the induction of donor-specific tolerance or immuno-isolation emerge as clinical strategies (Sperling, pp. 529-552).

The goal of islet transplantation is to infuse enough islets to control blood glucose level without insulin injection. A typical transplant requires about 1 million islets, extracted from two donor pancreases for an average-size person (70 kg). Because good control of blood glucose may slow or prevent progression of diabetic complications such as nerve or eye damage, a successful transplant may reduce the risk of these complications. But a transplant recipient still needs to take immunosuppressive drugs to stop the immune system from rejecting the transplantation. (Pancreatic, p. 1)

Researchers seek new approaches to allow successful transplantation without immunosuppressive drugs, "thus eliminating the side effects that may accompany their long-term use." (Ibid.)

Nine patients who became diabetic after upper-abdominal exenteration and liver transplantation were given pancreatic islet-cell grafts obtained from the liver donor (eight cases), a third-party donor (one), or both (four). Two of the diabetic patients died of infections after 48 and 109 days, and a third patient died of tumor recurrence after 178 days. The other 6 survived 101-186 days postoperatively, and five remained insulin-free or on insulin only during night-time parenteral alimentation. C-peptide increased 1.7 to 3.3 fold in response to intravenous glucose in these five patients who have had glycosylated hemoglobin in the high normal range. The kinetics of the C-peptide responses to intravenous glucose in all eight patients revealed no first-phase release and delayed peak response consistent with transplantation and/or engraftment of a suboptimal islet cell mass. "The longest survivor, who requires neither parenteral alimentation nor insulin, is the first unequivocal example of successful clinical islet-cell transplantation." (Tzakis, p. 1323)

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. Immunosuppressive drugs are needed to keep the transplanted islets functioning.

Immunosuppressive Drugs

The Edmonton protocol uses a combination of immunosuppressive drugs, also called antirejection drugs, including dacliximab (Zenapax), sirolimus (Rapamune), and tacrolimus (Prograf). Dacliximab is given intravenously right after transplantation and discontinued. Sirolimus and tacrolimus, the two main drugs that keep the immune system from destroying the transplanted islets, must be taken for life (Pancreatic, p. 1).

In the 35 years since the first vascularized (using blood vessels) pancreas transplant was performed in Minneapolis, Minnesota to prevent recurrent nephropathy (kidney disease) in a concomitant renal (kidney) transplant, an estimated 12,000 procedures have been performed in this country. This number is nevertheless insignificant compared to theā€¦