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.
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 the estimated one million patients with type 1 diabetes. However, what was once a slow journey has recently gathered momentum with the introduction of “more flexible immunosuppression protocols, the ability to individualize surgical options to patient needs, and the dramatic improvement of isolated islet transplantation results.” (Allen, p. 3485) Researchers use pancreas transplant options and advanced surgical techniques, but the donor pancreas and surgical complications, as well as the type of immunosuppression affect the outcome of islet transplantation.
The immunosuppressive drugs have significant side effects and long-term effects are still not known. Known side effects of immunosuppressive drugs include mouth sores and gastrointestinal problems, such as stomach upset or diarrhea. Patients also have experienced increased blood cholesterol levels, decreased white blood cell counts, decreased kidney function, and increased susceptibility to bacterial and viral infections. Taking immunosuppressive drugs increases the risk of tumors and cancer as well.
Progress on whole pancreas and beta cell transplantation has been hampered by the lack of available organs and the question of immunosuppression. The Center for Islet Cell Transplantation is a project with the goal of successful transplantation of beta cells without immunosuppression. Alternative approaches to islet transplantation under investigation include mixed bone marrow chimerism and co-stimulatory blockade. Another alternative to islet transplantation pursued for many years with varying success is the approach of shielding the islets from the immune system with a physical barrier while allowing the islets to receive nutrients and the insulin generating signals they need to produce the necessary insulin, then moving them through the barrier to the bloodstream. Techniques for accomplishing this include microencapsulation and a bioartificial pancreas. Other aspects that investigators are investigating include alloreactivity and autoreactivity. Also, who might benefit most from transplantation needs to be addressed (Clark, p. 52).
Insulin-secreting pancreatic beta cells derived from stem cells — pending availability — may be eventually transplanted into patients to help maintain blood glucose homeostasis. The relative success of the transplantation of cadaveric beta cells into patients with type 1 diabetes provides support for this approach (Stanier, p. 521)
An islet cell transplant may be an option for severe type 1 diabetes that can not be effectively managed with insulin or leads to complications. Because the procedure is still considered experimental in the United States, receiving it usually means participating in a clinical trial. Available organs usually are first allocated to people waiting to receive whole pancreas transplants.
If a patient is accepted into a trial, they will need to wait for a donor pancreas. If a match can not be made, an organ is then allocated to a person on the islet cell transplant list.
What happens during and after the transplant?
An islet cell transplant begins with technicians extracting and purifying islet cells from a donor pancreas. Often, two or more donor organs are needed to accumulate enough islet cells for a single complete transplant.
An interventional radiologist performs the actual islet cell transplant. This specialist and the radiologist direct a tube through an opening made in the abdomen to the portal vein, a blood vessel leading into the liver. They then infuse the islet cells through the tube to the liver, where the cells take up residence in the organ’s small blood vessels. The liver is a good site for the islet cell transplant because it is more accessible than the pancreas, and the cells produce insulin well in that environment (Mayo, p. 1). Possible risks during surgery include bleeding or blood clots.
After the transplant, the new islet cells need time to start working. The transplant team closely monitors blood sugar level and give insulin as needed. If the transplant is successful, the amount of insulin needed is gradually reduced as new cells take over.
Because the immune system may try to reject new cells, patients take medications that suppress the immune system. These medications may cause noticeable side effects, such as weight gain, acne, facial hair, stomach upset or diarrhea, but the effects decrease as time goes on.
The post-transplant treatment is a delicate balancing act between preventing rejection and managing unwanted side effects. A doctor monitors treatment of the patient closely and adjusts medication and care as needed. Intensive care also fosters higher success rates. (Mayo, p. 1) Clinical outcomes in terms of secondary complication rates were much better in the intensively treated group than in the conventionally treated group. Therefore, intensive treatment became the norm. More recent improvements in home care have also improved outcomes (Robertson, p. 694).
Intensive care includes pancreas and islet cell transplantation. In the 35 years since the first vascularized (with 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 islet transplantation procedures have been performed in the U.S. While this represents a major achievement, it is insignificant compared to the estimated one million patients with type 1 diabetes. The initially slow journey has gained momentum with the dramatic improvement of isolated islet transplantation results. With more flexible immunosuppression protocols, and the ability to individualize surgical options to patient needs, numbers have improved when intensive care is utilized (Allen, p. 3485).
A major obstacle to widespread use of islet transplantation is the shortage of islet cells. The supply available from deceased donors will be enough for only a small percentage of those with type 1 diabetes. Researchers pursue avenues of alternative sources, such as creating islet cells from other types of cells. New technologies may be employed to grow islet cells in the laboratory.
Limitations of Islet Transplantation
Published information shows several modifications of the Edmonton Protocol have been performed in over 15 centers involving over 160 patients worldwide. Patients who respond well to islet transplantation report being free of the need for insulin for about one year, on average, with the longest case being 7 years. This is similar to the rate of insulin independence achieved following whole pancreas transplantation.
Although results from clinical studies appear promising, there are significant issues that remain before the technique can be considered for widespread application: Limited islet supply remains an obstacle. Only a limited number are suitable for transplant, based on the number of pancreas donors in the United States each year.
Techniques to isolate islets have not been perfected (U.S.). Denise Faustman and colleagues at Massachusetts General Hospital (MGH) have an approach that identifies and selectively eliminates only the faulty cells of the immune system that mistakenly destroy healthy insulin-producing beta cells. The research has only been conducted on mice, but the Federal Drug Administration and the MGH have approved plans for a clinical trial to correlate the mouse model findings to type 1 diabetes in humans (4).
Immunosuppression toxicity: After receiving a transplant, patients receive potent immunosuppressive medications for the rest of their lives. These medications often have serious side effects, so patients also contend with a higher risk of infections resulting from a weakened immune system. Normal blood sugar levels are not achieved. Although islet transplant patients appear to have better control of their blood sugar levels compared to those who achieve it with insulin, diet, and exercise, only a small percentage of transplant patients achieve normal blood sugar levels.
Long-term safety numbers are questionable. Gaining access to the portal vein of the liver to transplant islet cells involves some risks as it is a difficult procedure. Immediate risks include portal vein thrombosis and bleeding. Long-term consequences are not known, but reports of hepatic steatosis have been documented. This happens when fat globules collect within the cells of the liver and cause the tissue to deteriorate and malfunction.
Duration of islet allograft function may be exhausted. In addition to rejection by a patient’s immune system, the transplanted islets are susceptible to aging. It is not known how long islets function after transplantation, and whether the patient may eventually need multiple transplants.
The effect of islet transplantation on diabetic complications remains a question. Controversy remains over whether a transplant actually stops or reverses secondary complications related to diabetes. It is also not clear whether transplantation may extend a patient’s long-term survival rate (U.S.)
Insulin independence is difficult to sustain with islet transplantation. The Edmonton protocol can successfully restore endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control. But even without insulin independence, persistent islet function following the procedure provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin (Shapiro, p. 1330). (ClinicalTrials.gov number, NCT00014911 [ClinicalTrials.gov].) Fortunately, there are alternative solutions to the rejection of islets by the immune system that are currently being researched.
Allen, R.D.M., et al. (January-February 2000). Pancreas and islet transplantation: an unfinished journey. Transplantation Proceedings. Vol. 33. Nov-Dec 2001.
Clark, W.L. (January-February 2000). Beta cell replacement and islet transplantation. Diabetes Self-Management. Vol. 17(1): pp. 52, 54, 56.
Collazo-Clavel, M., ed.. (2001). Mayo Clinic on Managing Diabetes. Rochester, MN: Mayo Clinic.
Faustman, D. (December 2004). Towards a cure for type 1 diabetes (and other autoimmune diseases?). Infocus. 12(4): 1.
Mayo Clinic Staff. (3 Oct 2006). Islet cell transplant: experimental treatment for type 1 diabetes. MayoClinic.com. Retrieved December 24, 2006 at http://www.mayoclinic.com/health/islet-cell-transplant/DA00046.
Pancreatic Islet Transplantation. (Nov 2003). National Diabetes Information Clearinghouse (NDIC). Retrieved December 24, 2006 at http://diabetes.niddk.nih.gov/dm/pubs/pancreaticislet/.
Robertson, R.P., (Feb 12, 2004). Medical progress: islet transplantation as a treatment for diabetes — a work in progress. New England Journal of Medicine 2004; Vol. 350.
Shapiro, a.M.J., et al. (Sep 28, 2006). International trial of the Edmonton protocol for islet transplantation. New England Journal of Medicine, 2006; Vol. 355.
Sperling, M.A., ed. (2003). Type I Diabetes: Etiology and Treatment. Totowa, NJ: Humana Press.
Stainier, D. (Feb 2, 2006). No stem cell is an islet (yet), clinical implications of basic research. New England Journal of Medicine 2006; Vol. 354: 521-523.
Tzakis, a.G., et al. (24 Nov 1990). Pancreatic islet transplantation after upper abdominal exenteration and liver replacement. Lancet, 1990, Vol. 336.
U.S. Food and Drug Administration. (10 Sep 2003). Pancreatic islet transplantation to treat Type 1 diabetes. Department of Health and Human Services. Center for Biologics Evaluation and Research. Retrieved December 24, 2006 at http://www.fda.gov/cber/genetherapy/pancislet.htm.
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