ISLET TRANSPLANTATION IN TYPE 1 DIABETIC PATIENTS USING THE EDMONTON PROTOCOL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Islet transplantation has been investigated as a treatment for Type 1 diabetes mellitus in selected patients with inadequate glucose control despite insulin therapy. However, the perennial hope that such an approach would result in long-term freedom from the need for exogenous insulin, with stabilization of the secondary complications of diabetes, has failed to materialize in practice. Of the 267 allografts transplanted since 1990, only 12.4% have resulted in insulin independence for periods of more than one week, and only 8.2% have done os for periods of more than one year. In the majority of these precedures, the regimen of immunosuppression consisted of antibody induction with an antilymphocyte globulin combined with cyclosporine, azathioprine, and glucocorticoids. The published observationd by Shapiro, et al. from Edmonton, from a series of seven consecutive subjects with Type 1 diabetes, indicate that islet transplantation can result in insulin independence with excelent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass. In that series, all seven subjects quickly attained sustained insulin independence after percutaneous transhepatic portal vein transplantation of islets. All recipients required islets form two donor pancreases, and one required a 3rd transplant from two donors to achieve sustained insulin independence. Nearly all donor pancreata were previously rejected as suitable for whole organ transplant before being subject to the islet isolation procedures. There were no further episodes of hypoglycemic coma following transplant. Complications were minor, and there were no significant increases in lipid concentrations during follow-up. In an update to this published report, a total of 10 consecutive subjects have now remained insulin independent following islet cell transplant and use of a glucocorticoid-free immunosuppressive protocol that includes sirolimus, low-dose tacrolimus, and a monoclonal antibody against the interleukin-2 receptor (daclizumab). This multi-center feasiblity study is designed to determine the reproducibility of the preliminary success obtained at a single center (Shapiro, et al., University of Alberta in Edmonton). This will be determined by provideing the participated centers with training and standardized criteria and procedures for subject selection, cadaveric donor qualifications islet cell processing, islet transplantation, and post-transplant treatment regimens. A total of 40 subjects at up to 10 centers are to be enrolled under this protocol. The duration of follow-up is intended to last for 1 year after the second (or final) transplant and the study should last about 2 years. The schedule of follow-up visits and evaluations is shown in Appendix 1.