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By Camillo Ricordi, MD
Scientific Director, Diabetes Research Institute
University of Miami
The immediate goal of islet cell transplantation is to achieve the same level of success as pancreas transplants. This would allow patients to receive only the cells needed to normalize blood glucose and would not require major surgery nor the potential risks associated with whole pancreas transplantation. The challenge for scientists is to develop standardized approaches that will enable safe, consistent, long-term islet function.
Scientists are now pursuing xenotransplantation (pig or other non-human sources of islets), genetically engineered cell lines and regeneration and/or cell expansion strategies as sources of islets to transplant into people with diabetes. Until one or more of these techniques is perfected, human donor organs are essential in the short term to make islet transplantation a viable therapy for all those with type 1 diabetes.
Today, in the United States, UNOS (United Network for Organ Sharing) gives priority to whole-organ transplants over islet cell transplants, which means that whole pancreases will be donated rather than just the islets. However, UNOS is now collaborating with islet transplant researchers to change the allocation rules for pancreases. For now, UNOS will enable selected islet transplant protocols to be tested on a limited number of patients until we can prove the real promise of the strategies proposed.
Mounting Evidence of Success
There is mounting evidence that islet cell transplantation will work as a therapy to normalize blood sugar levels in patients with type 1 diabetes. The unprecedented advances during the past few years have created renewed interest and enthusiasm throughout the scientific community and, of course, among patients and families living with diabetes. This excitement is due in large part to the recent improvement of clinical islet transplantation (using unrelated, adult human islets) and the ability to achieve and maintain insulin independence in more than 33 immunosuppressed patients with type 1 diabetes. It has also been shown that transplanted islet cells can function for more than eight years and, even in those cases with only partial islet function, normalized blood sugar levels have been easily achieved with small doses of insulin, virtually eliminating the risk for severe hypoglycemic episodes.
It is important to note that this progress was achieved in patients requiring a traditional "cocktail" of immunosuppressive drugs to prevent organ transplant rejection. These traditional antirejection drugs are diabetogenic; that is, they cause the elevation of blood sugar and therefore increase the metabolic demands on the recipient's new islet cells. This has been one of the factors hampering the success of islet transplantation.
New drugs, however, are being developed, and appear to be safer and more effective in preventing immune rejection and may also favor other factors required for successful engraftment of transplanted islet cells.
Recent results from our studies with non-human primates (made possible through funding from the Diabetes Research Institute Foundation [DRIF]) have clearly demonstrated the potential of these new drugs. Using new drugs, including one called anti-CD154, we have been able to establish and maintain insulin independence in monkeys for more than one year. These encouraging results have produced renewed enthusiasm in the field.
The Juvenile Diabetes Foundation International (JDFI) and the National Institutes of Health (NIH) have now launched significant initiatives to support more non-human primate studies, as well as clinical trials of islet transplantation. Based on these striking results, a limited pilot clinical trial is now starting here at the University of Miami and at the University of Minnesota using the same drug. At the same time, other centers in the United States, Canada and Europe are testing islet antirejection drug combinations that are less toxic to the islets. The data from these studies will provide additional information to further develop strategies to improve graft acceptance and long-term function.
Now, more than ever, islet transplant centers are working as a team to standardize procedures for clinical testing in multicenter trials. We are grateful to the NIH, JDFI and the DRIF for their funding. With their help we have a definite opportunity to make islet transplantation a reality. Failure is not an option.
By Bernhard J. Hering, MD
Head, Islet Transplantation Program
University of Minnesota
The year 1999 marks a turning point in the history of islet cell transplantation for the treatment of type 1 diabetes.
Funding of clinical islet transplant trials
The initiative funded by the JDFI and the NIH which Dr. Ricordi mentions will be called the Collaborative Network for Clinical Research on Immune Tolerance. The JDFI, the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute for Allergy and Infectious Diseases (NIAID) [both parts of the NIH] have made available substantial funding to support innovative clinical trials of islet transplantation in people with type 1 diabetes. It is hoped that funding agencies based in Europe will also provide funding needed for the translation of promising experimental findings into the clinic. [See page 22 for full story.]
The objective of this network, an immense, seven-year research initiative, is to capitalize on the extraordinary opportunities now available in the areas of transplantation and to translate promising research into practical benefits for transplant recipients and people suffering from autoimmune disorders. Leading scientists and clinicians from around the world will closely collaborate to develop protocols that will allow the transplantation of organs without the need for continuous immunosuppression as well as the elimination of autoimmunity. This network is uniquely positioned to expedite the development of islet transplantation.
Prospective multicenter trials
The experience in clinical islet transplantation is largely based on reports from one hospital or university working on its own. The network, as well as collaboration with pharmaceutical companies, will provide statistical leadership and clinical trial design expertise critically needed to evaluate new strategies.
Safer antirejection therapy
The failure to achieve insulin independence in previous islet transplant trials has been ascribed to the use of diabetogenic (hindering the secretion and action of insulin) antirejection drug regimens. Now, for the first time, new agents have become available that have the potential of eliminating steroids completely. The first agent is rapamycin, a new immunosuppressant recently approved by the FDA for the prevention of kidney transplant rejection in combination with cyclosporine. Rapamycin is a unique agent because it works with cyclosporine, reducing the amount of cyclosporine needed. This combination decreases the incidence of rejection episodes and facilitates steroid avoidance or withdrawal. It seems possible, if not likely, that the correct use of rapamycin combined with low doses of cyclosporine (or tacrolimus) will restore and maintain insulin independence in islet transplant recipients without harmful side effects. Clinical trials are currently underway at the University of Alberta.
As mentioned by Dr. Ricordi, anti-CD154 has also shown promise. These two developments signal a quantum leap in our approaches to prevent rejection of islet transplants in people with type 1 diabetes. Results of clinical trials are awaited with great interest.
Islet transplantation before kidney failure
Clinical trials in islet transplantation are no longer restricted to recipients of kidney transplants. To date, the majority of islet transplants have been performed in those who already need a kidney transplant. The thinking is that these people will need antirejection drugs anyway so they should receive an islet transplant along with a new kidney. The prevailing view is that potentially harmful antirejection drugs cannot be justified in a transplant of islets only.
There is now increasing agreement that new antirejection drugs should be tested in solitary islet recipients. The new drugs, with fewer side effects, support this approach. The advantage of this approach is that antirejection protocols are no longer dictated by the requirements of the kidney transplant and can rather be targeted to the special and fundamentally different complexities of islet cell transplantation. Typically, eligible recipients are individuals age 18 and older in whom type 1 diabetes is complicated by severe metabolic instability (wide swings in blood sugar, including frequent hypoglycemic episodes), symptomatic autonomic or peripheral neuropathy or a very poor quality of life despite continued and intensive efforts made in close cooperation with a certified diabetes care team.
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