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. The objective of this application is to utilize GCRC resources for use of freshly isolated human pancreatic islets for the treatment of type 1 diabetes. Islet allografts have been performed in nearly 400 patients with type1 diabetes since the early 1970's, but prior to the 'Edmonton experience', only forty-one recipients of this cohort had achieved insulin independence following transplantation. Islet transplantation as a treatment for type1 diabetes took a dramatic step forward with successes reported at the University of Alberta in Edmonton. This group demonstrated consistent reversal of Type1 diabetes following sequential islet transplantation from two donor pancreases and subsequent immunosuppression with a novel, steroid-free regimen including interlukin-2 receptor antibody daclizumab, sirolimus, and low-dose tacrolimus. The rationale behind the Edmonton approach had been to maximize the potential for insulin by titration of an adequate islet transplant mass so that the potential side effects of immunosupression are outweighed by the benefits of insulin independence and tight glycemic control. The success of the Edmonton Protocol has provoked the creation of an NIH-funded clinical trial (the Immune Tolerance Network Islet Transplant Trial enlisting 10 centers worldwide to emulate the methodology of the U of Alberta),the development of Islet Transplant Centers funded by the Juvenile Diabetes Research Foundation, and the development of 'Islet Cell Resource Centers' (ICRs) funded by the NIH (NCRR) to optimize the use of each pancreas for potential transplant. Our center, the University of Colorado Health Sciences Center, was one of 10 centers selected for participation as an Islet Cell Resource Center. At present, our laboratory has gained NIH approval for islet isolation under cGMP guidelines and has performed 41 pancreatic islet isolation procedures over 18 months. Our facility is now prepared to move toward clinical use of our human islet preparations. We plan to emulate the Edmonton protocol as a standard from which to assess function and outcomes of islet transplantation prior to transitioning to novel treatment protocols and patient populations. The objective of this study is to assess the safety and efficacy of islet allotransplantation for the re-establishment of stable glycemic control in patients with type 1 diabetes in an open-label, single-center pilot trial. Potential candidates for islet allotransplantation will include patients greater than or equal to 18 years of age with type 1 diabetes in whom metabolic liability/instability, reduced awareness of hypoglycemia, progressive secondary complications despite intensive management, in cooperation with their diabetes care team. Adverse events will be monitored and recorded throughout the first two years post-transplant. The proportion of type 1 diabetic islet allograft recipients with full (insulin independence and HbA1c<7%) and partial (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5ng/mL and glycated hemoglobin less than or equal to 7%) islet graft function at one year post transplant and beyond will be assessed.
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