ANTI-THYMOGLOBUMLIN, CYCLOSPORIN AND RAD IN ISLET TRANSPLANT

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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. This is a Phase I/II study designed to assess the safety and efficacy of sequential islet allotransplantation for the reestablishment of stable glycemic control in trype 1 diabetic recipients. A total of 6 patients with type 1 diabetes will be enrolled to receive two, possibly three transplants of islets from different donor pancreases. Potential candidates for islet allotransplantation will include patients age 18 and older with trype 1 diabetes. Induction immunotherapy for the first transplant will consist of anti-thymocyte globulin; basiliximab will be used for any subsequent transplants. Peritransplant anti-inflammatory treatment with etanercept will be given for each islet transplant. Maintenance immunosuppression will be with cyclosporine and RAD. It is felt that those patients in whom metabolic lability/instability, reduced awareness of hypoglycemia, poor glycemic control, and progressive secondary complications persist despite continued and intensive efforts made in close cooperation with their diabetes care team are particularly likely to have a favorable benefit/risk ratio. Adverse events, irrespective of their presumed relationship to the transplantation of allogeneic islets and/or protocol-regulated treatment products (concomitant therapy), will be monitored and recorded throughout the first year after the final islet transplant. The proportion of subjects who achieve insulin independence in the first year after the first, second or third allogeneic islet transplant will be assessed in a prospective trial. In the event insulin independence is not achieved within the first 6 weeks after islet transplantation, a second and possibly a third transplant will be performed. The proportion of single and sequential donor 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 0.5 ng/mL and HbA1c <= 7%) islet graft function at one year after the final islet transplant will be assessed. The impact of islet transplantation on quality of life will also be assessed. The predictive value for posttransplant insulin independence of factors such as insulin resistance before and at intervals after pancreatectomy, cellular composition of the transplant, number of beta cells transplanted; and viability and insulin secretory response of isolated islets will be assessed. The GCRC will be asked to provide the structure necesary to conduct this clinical research protocol. We will use both the in and out patient beds in carrying out this protocol. Patients will be admitted to CRC two days prior to islet cell transplant (day-2) to begin the immunotherapy required for this protocol. They will remain as inpatients on CRC until day 2 post transplant for post islet transplant recovery, monitoring and continuation of immunotherapy. Patients will return to the CRC as outpatients for 15 post transplant follow up visits. The CRC nursing staff is needed to provide the careful monitoring necessary to maintain blood glucoses in the normoglycemic range pre and post transplant. Nursing expertise will also be relied on for precise collection of specimens and careful monitoring of patients after their islet transplant procedure and follwoing administration of immunotherapy.