Islet Transplantation: Where Will It Go From Here?
Reviewed by Jennifer B. Marks, MD
Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immuno-suppressive regimen. N Engl J Med 343:230-38, 2000.
Objective. The objective of this study was to test the effectiveness of a glucocorticoid-free immuno-suppressive regimen in conjunction with islet transplantation in individuals with type 1 diabetes.
Design and Methods. Seven patients who had type 1 diabetes for >5 years, uncontrolled despite compliance with an insulin regimen, were eligible to undergo islet transplantation. Immunosuppression was initiated immediately before transplantation using sirolimus (Rapamune), low-dose tacrolimus (Prograf), and a monoclonal antibody against the interleukin-2 receptor, daclizumab (Zenapax). No glucocorticoids were given at any time during the trial.
As soon as sufficient numbers of islets were available for transplantation, patients were given prophylactic intravenous antibiotics (vancomycin and imipenem), and oral supplementation with vitamin E, vitamin B6, and vitamin A was started. Inhaled pentamidine (for PCP prophylaxis) was given once a month after transplantation, and oral ganciclovir was given for 14 weeks to reduce the risk of graft loss and protect against lymphoproliferative disorder.
Patients received an average of 800,000 islet equivalents, transplanted immediately after isolation via transhepatic injection into the portal vein. Donors were selected according to the results of a multivariate analysis of factors that influence the success of islet isolation,1 matched for blood type and lymphocytotoxic antibodies but not HLA.
Insulin therapy was discontinued after each transplantation and not resumed unless serum glucose concentrations rose above 200 mg/dl, in which case another transplant was performed. Blood glucose levels were checked seven times per day. Patients also underwent oral glucose tolerance testing. HbA1c and C-peptide levels were also measured.
Results. All seven patients quickly attained sustained insulin independ-ence (median follow-up 11.9 months, range 4.414.9). All recipients required islets from two donor pancreases, and one required a third transplant from two donors. The mean HbA1c values were normal in all transplant recipients. The amplitude of blood glucose fluctuations was dramatically decreased, and further episodes of severe hypoglycemia, common before transplantation, did not occur. Detectable C-peptide levels were measurable at 3 and 6 months. Glucose tolerance was not completely normalized; whereas none of the recipients had diabetic oral glucose tolerance tests, five had impaired glucose tolerance, and two had impaired fasting glucose.
Investigation of pancreatic islet cell transplants as a potential procedure to reverse diabetes has been ongoing since the early 1970s. However, success in humans has been elusive for a variety of reasons.1,2 Of the 267 allografts transplanted since 1990, only 12.4% of the recipients have remained insulin-independent for longer than 1 week and only 8.2% for longer than 1 year.3
Now this study from the University of Alberta in Canada reports impressive resultsreproducible success in seven islet transplant recipients who remain insulin-independent for a median follow-up of nearly a year. Is this the "cure" for which so many have worked so long and hard? It is important to try to understand why this group achieved such success.
Most importantly, there are significant differences in the procedures used by the Edmonton group compared with other protocols. Carefully selected, high-quality islets in approximately twice the number used in other protocols were transplanted fresh and as soon as possible after harvesting.
The conventional immunosuppressive regimen was drastically modified, eliminating the use of glucocorticoids, substantially lowering the dose of tacrolimus, and adding daclizumab. All of these changes in the usual approach were likely to have had an impact. Glucocorticoids, higher-dosage tacrolimus, and cyclosporine, used in many earlier protocols, are known to have adverse effects on -cell function and survival. Glucocorticoids may also be diabetogenic because of effects on increasing peripheral insulin resistance, creating a greater demand on -cells.
Several specific questions immediately arise from the striking results presented here. Will the treatment success last? Can the results be reproduced by other investigators? What, if any, effects will result from this immunosuppressive regimen?
But even beyond these immediate questions, hopefully to be answered by the comparable multicenter protocols now in the planning stages, this study should be considered a "landmark" as much for the myriad of broader issues it raises, which will need to be addressed. Assuming success is reproduced, where will all the islets come from? The demand for islets and whole pancreases now outstrips the supply. This protocol used two pancreases per recipient. Can that be improved upon? Who will be eligible recipients? With a limited supply, specific criteria will likely need to be determined. Who will determine such criteria? Will it be appropriate to consider transplantation for patients with type 2 diabetes? Should more research effort be going toward improving the results of pancreas transplantations, successful now at achieving long-term insulin independence in 7090% of recipients?4
Thus, this study is a landmark from many points of view. Whereas everyone is eager for its success to be reproduced, it is clear that new problems and issues will arise from such success, and these will have to be met and dealt with. This study represents one fork in the lengthy road leading to the eradication of diabetes, which may be accomplished by prevention or cure. We will all be closely watching these next few years to see where the path that islet transplantation carves out will lead.
1Lakey JRT, Warnock GL, Rajottee RV, Suarez-Almazor ME, Ao Z, Shapiro AMJ, Knetemen NM: Variables in organ donors that affect the recovery of human islets of Langerhans. Transplantation 61:1047-53, 1996.
2Hering BJ, Ricordi C: Islet transplantation for patients with type 1 diabetes. Graft 2:12-27, 1999.
3Brendel M, Hering B, Shulz A, Bretzel R: International Islet Transplant Registry Report. Giessen, Germany: University of Giessen, 1999, p. 1-20.
4Tibell A, Christiansen E, Groth CG: Pancreas transplantation. In International Textbook of Diabetes Mellitus. 2nd ed. Alberti KGMM, Zimmett P, DeFronzo RA, Eds. Chichester, England, John Wiley & Sons, 1998, p. 981-90.
Jennifer B. Marks, MD, is an associate professor of medicine in the Division of Diabetes, Endocrinology, and Metabolism at the University of Miami School of Medicine and chief of the Diabetes, Endocrinology, and Metabolism Division at Miami's VA Medical Center.
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