Following the success obtained with transplantation of fresh human islets under steroid-free immunosuppression, this trial evaluated the transplantation of islets that had undergone a period of in vitro culture and the potential of tumor necrosis factor (TNF-a) blockade to improve islet engraftment. Subjects included 16 patients with type 1 diabetes mellitus (T1DM); half were randomly assigned to receive Infliximab immediately preceding initial infusion. Immunosuppression consisted of daclizumab induction and sirolimus/tacrolimus maintenance. Out of 16 subjects 14 achieved insulin independence with one or two islet infusions; adverse events precluded completion in two. Without supplemental infusions, 11/14 (79%) subjects were insulin independent at 1 year, 6/14 (43%) at 18 months; these same subjects remain insulin independent at 33 ± 6 months. While on immunosuppression, all patients maintained graft function. Out of 14 patients, 8 suffered chronic partial graft loss, likely immunological in nature, 5 of these received supplemental infusions. Currently, 11 subjects remain on immunosuppression, 8 (73%) are insulin independent, two with supplemental infusions. Insulin independent subjects demonstrated normalization of HbA1c, fructosamine and Mean Amplitude of Glycemic Excursions (MAGE) values. No clinical benefit of infliximab was identified. These results demonstrate that transplantation of cultured human islet allografts results in reproducible insulin independence in all subjects under this immunosuppressive regimen, comparable to that of freshly transplanted islets (Edmonton protocol).

This study analyzed quality of life in patients with type 1 diabetes that received islet transplantation. Twenty-three subjects were followed over 3 years. In addition to an interview, patients self-completed two standardized psychometric questionnaires, HSQ 2.0 and DQOL, before and after transplant, and scores were compared. Analysis was also adjusted for potential "confounders" such as graft dysfunction, insulin therapy and adverse events. DQOL: the Impact score significantly improved at all time points of the followup; satisfaction and worry scales also significantly improved at selected time points. Longitudinal analysis demonstrated that reintroduction of insulin had a negative effect on all three scales, but significant improvement in Impact scale persisted even after adjusting for this factor. HSQ 2.0: only the Health Perception scale preliminarily showed significant improvement at most time points. Longitudinal analysis showed loss of significance when insulin therapy was considered. Other scores were improved only at selected time points or not affected. Bodily pain scale showed deterioration at selected times. Interview: glucose control stability, not insulin independence, was reported as the main beneficial factor influencing QOL. In conclusion, islet transplantation has a positive influence on patients' QOL, despite chronic immunosuppression side effects. Re-introduction of insulin modifies QOL outcomes.

In order to make islet transplantation a therapeutic option for patients with diabetes there is an urgent need for more efficient islet cell processing to maximize islet recovery. Improved donor management, organ recovery techniques, implementation of more stringent donor criteria, and improved islet cell processing techniques may contribute to enhance organ utilization for transplantation. We have analyzed the effects of donor and islet processing factors on the success rate of human islet cell processing for transplantation performed at a single islet cell processing center. Islet isolation outcomes improved when vasopressors, and in particular pitressin, and steroids were used for the management of multiorgan donors. Higher islet yields were obtained from adult male donors, BMI >25 kg/m 2 , adequate glycemic control during hospital stay, and when the pancreas was retrieved by a local surgical team. Successful isolations were obtained in 58% of the cases when ≥ 4 donor criteria were met, and even higher success rates (69%) were observed when considering ≥ 5 criteria. Our data suggest that a sequential, integrated approach is highly desirable to improve the success rate of islet cell processing.Key words: Pancreatic islets; Islet transplantation; Organ selection; Islet isolation; Donor management; Pancreas preservation; Pancreas recovery; Islet purification INTRODUCTION deceased donor pancreata. There is an urgent need for the definition of more stringent donor selection criteria that could help maximize the success rate of human islet Transplantation of allogeneic pancreatic islets can improve metabolic control and quality of life in patients cell processing (27,33,39,41,43,46,72). The use of regional islet cell processing centers supporting clinical with unstable type 1 diabetes (T1D) (11,13,46,47,49, 59,62). Insulin independence is generally achieved by islet transplant programs (CITP) at remote sites has proven effective in this direction (14,23). transplanting ϳ12,000 islet equivalents (IEQ)/kg of recipient body weight (11,49,59,62). Sufficient islet numIn the present study, we have analyzed the effects of donor and islet processing factors on the success rate of bers can be obtained from a single donor (11,19,62,63), but generally more than one islet preparation per recipihuman islet cell processing for transplantation performed at a single islet cell processing center. ent is required to observe insulin independence after transplantation (11,14,32,59,62). Steady progress has been obtained in recent years thanks to improved organ MATERIALS AND METHODS recovery and preservation methods (9,26,28,50), and isPancreas Procurement let isolation and purification techniques (1,22,29,52). The high islet numbers required to achieve insulin indePancreata were obtained from multiorgan, deceased donors ( (2,11,12,14). Additional organs were most of the critical steps of cell processing (namely, duct cannulation, pancreas trimming, and decision on obtained through the Texas Organ Sharing Network under an ongoing part...

There was a varying range of AEs, most of them mild and self-limiting; however, some required urgent medical attention. The majority of patients were able to tolerate and remain on this effective regimen. To date, no deaths, cytomegalovirus disease, graft-versus-host disease, or posttransplant lymphoproliferative disease has been observed.

Background Progressive graft dysfunction (GDF) and loss of insulin independence (II) has been invariably observed in islet transplant recipients under the ‘Edmonton protocol’. To reestablish II we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial. Methods Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed over 18–month follow-up. Results Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-Control (p=0.04). SI-EXN subjects demonstrated restoration of function better than that seen following initial islet infusions. Comparison of SI-EXN and SI-Control groups demonstrated better responses in SI-EXN subjects at three months post SI. Over the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-Controls. Acute effects of exenatide during MMTT and IVGTT results in improved first and second phase insulin release in response to intravenous glucose (IVGTT), and suppressed postprandial hyperglucagonemia after mixed meal tolerance test (MMTT). Conclusion These results suggest that the combination of exenatide and etanercept improve engraftment and long term islet survival and function in subjects undergoing SI. This data however must be interpreted with some caution due to small sample size, lack of randomization and sequential comparison with historical controls.