Islet Transplantation: Steeple Chase and the Next Hurdle

The history of islet of Langerhans transplantation can be seen as a steeple chase race against diabetes, and its latest hurdle was passed with elegance and panache when Shapiro et al. first reported on the success of what is widely known as the Edmonton protocol. The achievements of the protocol are known and reproducible: a rate of insulin-independence of about 80% at 1 year, at the cost of dual-donor islet transplantation in general, and a drop to approximately 10% at 5 years, albeit with residual islet graft function and improved metabolic control in most patients (1). However, the race is not over yet, and the next obstacles are clearly in sight: How to achieve consistent success with single donor transplantation, without having to resort to overselection of donor or recipient? How to understand, and thus avoid, islet graft loss in the early years after transplantation, in order to achieve consistent long-term function? These two issues are looming large in the field of islet transplantation, and have been extensively discussed in an excellent Forum in an earlier issue of Transplantation (2, 3). Another issue, perhaps of lesser long-term importance but nevertheless of immediate significance, regards the need to decrease the incidence and intensity of the morbidity of the procedure. But how significant is the morbidity of islet transplantation exactly? Although one earlier study suggested that the side effects incurred by the recipients might exceed the current benefits of islet transplantation (4), no in-depth risk/benefit analysis of the procedure, as it stands today, is as yet available. The excellent and very timely report from the group at the University of Miami published in this issue of Transplantation provides a comprehensive review of the complications experienced by a large series (by the standards of the method) of islet transplant recipients at a single center. Two distinct types of complications can be recognized: technical morbidity, resulting from the islet infusion procedure itself, and pharmaceutical morbidity such as side effects and complications of the immunosuppressive regimen. Technical morbidity is rather benign in the Miami series, with a low incidence of bleeding related to percutaneous puncture of the liver and no occurence of portal vein thrombosis. Liver bleeds, sometimes requiring surgical intervention, and portal vein thrombosis have been the classic complications of percutaneous intraportal islet infusion (5). Pharmaceutical morbidity looks disturbingly more problematic. By and large, a steroid-free combination of high-dose sirolimus, low-dose tacrolimus, and anti-IL2-receptor antibodies has been used by islet transplant programs. A large array of side effects is reported by the authors: mouth ulcers, hematologic abnormalities, dyslipidemia, gynecologic, neurologic and musculoskeletal disorders, peripheral edema, gastrointestinal disturbances, skin lesions, and kidney function impairment. Most infectious episodes have been self-limited. Significant opportunistic infections have been uncommon, notably no cytomegalovirus disease was observed, but one parvovirus infection led to immunosuppression withdrawal. In fact, the reported morbidity rate reaches 100% because all patients experienced at least one side effect. These side effects, most of them sirolimus-related, are sometimes poorly tolerated or life-threatening, and have led to immunosuppression withdrawal and graft loss in a few instances, an experience shared by most groups involved in clinical islet transplantation. So, are we overimmunosuppressing our patients? Do we have any leeway to attempt to reduce the rather high sirolimus levels we believe we need? Using this drug combination, probably not¡ In the multicenter trial sponsored by the Immune Tolerance Network, the single most significant determinant for early islet graft loss was the failure to achieve sirolimus target trough levels (A.M.J. Shapiro, 2003 American Transplant Congress, Washington, DC). One reason for the rather high immunosuppression required for islet graft maintenance probably lies in the double immunologic barrier, allogeneic and autoimmune, that must be confronted in this setting. Therefore, with the toxicity/side effect profile of the Edmonton regimen, islet transplantation cannot be seen and performed as a mere trade-off between insulin and immunosuppression, and candidates must be carefully selected so that their quality of life can be clearly improved by the procedure. Without appropriate selection of recipients with severe hypoglycemia unawareness and/or hypoglycemic events, a significant rate of failure, due to dropping-out or lack of compliance, can be anticipated. This is, of course, a consideration peculiar to islet transplant alone, which has become the foremost islet transplantation type performed. This does not apply as plainly in the simultaneous islet-kidney or islet-after-kidney situations, in which recipients are immunosuppressed anyway for their kidney transplant. This being said and considered, there is an immediate need to reduce the toxicity of the immunosuppressive regimen required for islet transplantation (6). Steroid avoidance has been a key determinant in the success of the Edmonton protocol, but further steps need be taken. The side effects of the largely sirolimus-based regimen have been outlined above. Although calcineurin inhibitor (CNI) doses currently used are quite low, concerns remain about their diabetogenicity and kidney toxicity. In particular, the sirolimus-tacrolimus combination is increasingly associated with impaired renal function, mainly because of CNI nephrotoxicity is potentiated by sirolimus (7). This is particularly worrisome in patients with the terrain of nephropathy that accompanies type 1 diabetes. An additional and intriguing detrimental effect of sirolimus might reside in its antiproliferative properties, which could prevent beta cell regeneration and contribute to long-term islet graft extinction. Until immune tolerance is reached, novel immunosuppressive regimens should be designed, primarily by minimizing or avoiding altogether CNIs and/or mTOR inhibitors. With the available pharmacopoeia, this could be achieved by putting the emphasis on T-cell-depletion in the induction period (thymoglobulin, hOKT3 γ1 (ala-ala), anti-CD3 immunotoxin, Campath-1H, rituximab) or using other classes of immunosuppressants such as mycophenolate mofetil, deoxyspergualin, or the novel agents FTY-720 or LEA-29Y (CTLA4-Ig). Some of these new compounds have already been used in nonhuman primate models with promising results, and will be tested in human trials shortly. Overall, in this wealth of new immunosuppressants, the short-term goal is to identify which association will provide our patients with an optimized regimen that will be gentle on the transplanted islets and devoid of excessive toxicity and side effects, while still protecting the graft from immune aggression.

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