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.