Immunosuppression and Islet Transplantation
Immunosuppressive therapy is necessary for all transplant recipients in order to prevent immune system rejection of foreign tissue present in grafts. In the case of islet cell transplantation for the treatment of Type 1 Diabetes, there is the added complication of preventing autoimmune rejection of the new cells. In view of this issue and of the unfortunate diabetogenicity of many immunosuppressive medications, it is no wonder that it took 36 years from the discovery of the first effective immunosuppressant for researchers to determine how to reliably prevent the rejection of islet transplants.
Type 1 diabetes is an autoimmune disease which causes the body to attack healthy islet cells, a problem that can continue with transplanted islets. This process should be distinguished from allogeneic immune responses, which occur when the body's immune system attacks tissue grafts because it does not recognize the surface antigens on the foreign cells.
This difference is highlighted by cases of identical twin donors and recipients. Normally, a graft recipient will not need immunosuppressants when he receives an organ from his identical twin because the cells in the graft will express the same surface antigens as the cells in his own body. However, a diabetic patient's immune system will still reject islet cells taken from his twin due to the autoimmune nature of the disease. In fact, researchers strongly suspect that the majority of islet cell graft rejections are autologous rather than allogeneic.
In order to be effective, islet cell transplantations must be accompanied by medications that prevent autologous and allogeneic immune rejection and that do not have diebetogeneic or, ideally, nephrotoxic side effects. The failure of the immunosuppressants used in early islet transplant trials to meet these criteria ultimately played a crucial role in their failure.
In the early days of transplantation, surgeons relied on a combination of azathioprine, an anti-mitotic agent, and corticosteroids, which disrupt T-cell activation. In 1974, these medications were used during the first islet transplants. Not surprisingly, the trials were failures; not a single patient managed to achieve insulin independence. Later trials were able to realize some degree of success by improving islet purification methods and by switching from azathioprine to cyclosporine, which is much less toxic. However, the continued problem of autoimmunity, combined with the transplanted islets' vulnerability to the toxic effects of immunosuppression, kept these gains modest.
The Edmonton protocol eliminates the use of these medications, instead using sirolimus and low doses of tacrolimus, and daclizumab. Sirolimus, which prevents rejection by inhibiting antigen induced proliferation of T cells and antibodies, has been found to be a superior medication for preventing autoimmune islet rejection without diabetogeneic side effects. This efficacy is further enhanced by adding small doses of other immunosuppressants. Tacrolimus, like cyclosporine, is a calcineurin inhibitor and is slightly toxic to the islets, which is why it is only used in small amounts. Daclizumab fulfills the same function as the corticosteroids, but without the same level of toxicity. Overall, the Edmonton group found this combination of drugs to be very effective, both because of its lower toxicity and because of its superior autoimmune suppression. These factors were critical to the Edmonton protocol's successes in a field dominated by failures.
There are two main problems with this method of treatment. One is the often serious side effects of sirolimus, which include mouth ulcerations, cholesterol and lipid problems, bone marrow damage, and pneumonia. The second is tacrolimus toxicity, which is believed, over time, to destroy the islet cells. For these reasons, many investigators are testing new medication protocols in an attempt to offer islet transplants with fewer complications.
Some researchers are also examining a technique called immunoisolation as a means to prevent immune rejection without the use of immunosuppressants. This approach entails isolating the transplanted cells in semipermeable membrane capsules. In theory this is an ideal solution, as the membrane would allow nutrients and insulin to pass in and out of the capsule while preventing the recipient's antibodies from coming into contact with the islets. In practice, however, these capsules typically fail within months of transplantation due to cell overgrowth and to macrophages produced by the overgrowth. At the present time, immunoisolation does not present a viable alternative to immunosuppression. Further research in this area is needed to determine the plausibility of this approach being a solution for islet rejection in the future.
Fig. 1 Mechanisms of rejection of transplanted islets
Immunosuppression vs. insulin therapy in the treatment of type I diabetes: examining the trade-off
It is unfortunate that most researchers studying islet transplantation have failed to address the question of whether the advantage of insulin independence is worth the side effects of immunosuppression. In early trials, recipients of islet transplants included only those who had also received kidney transplants and would require immunosuppression anyway. However, the Edmonton Protocol has focused on patients who are not receiving kidney transplants.
All three immunosuppressant medications used for islet transplantation can cause severe side effects, including diarrhea, vomiting, fever, nausea, tremors, swelling of the limbs, weakness, and numerous other problems. In addition, the immunosuppressant daclizumab must be injected, so patients who achieve insulin independence are not completely free from needles.
A major advantage of islet transplantation is that patients need not constantly monitor their blood sugar levels, as the transplanted cells will adjust their insulin output in response to changes in blood sugar levels. Each immunosuppressive medication is taken once a day, while patients on insulin therapy often must test their blood and inject insulin several times a day.
However, on the whole, insulin therapy is effective for most type 1 diabetics. Although this population can suffer from hyperglycemia, high blood pressure, and coronary problems, the side effects of immunosuppression are often worse. It is possible that the immunosuppressive regimens of the future will have fewer side effects, tipping the scales in favor of islet transplantation, but for now, this new therapy should be reserved for type 1 diabetics who are either suffering severe symptoms that insulin therapy cannot alleviate or who are receiving immunosuppressive drugs for some other reason.
References:
- Berney T, Buhler LH, Mentha G, Morel P. Immunosuppression for pancreatic islet transplantation. Transplantation Proceedings 2004;36:362S-366S
- Starzl, TE. History of clinical transplantation. World Journal of Surgery 2000;24:759-782
- Hering BJ, Wijkstrom M. Sirolimus and islet transplants. Transplantation Proceedings 2003;35:187S-190S
- Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplantation Proceedings 2003;35:7S-14S
- De Groot M, Schuurs TA, Leuvenink HGD, van Schilfgaarde R. Macrophage overgrowth affects neighboring nonovergrown encapsulated islets. Journal of Surgical Research 2003;115:235-241
- http://www.nlm.nih.gov/
Image References:
Fig. 1: http://www.insulinfree.org/islets/gray_fig3.htm
