CLINICAL ISLET TRANSPLANTATION

S. Matsumoto¹, M. Takita¹, H. Noguchi¹, M. Shimoda², K. Sugimoto¹, T. Itoh¹, D. Chujo³, N. Onaca⁴, B. Naziruddin⁴, M.F. Levy^4
1Islet Cell Laboratory, Baylor Research Institute Fort Worth Campus, Fort Worth/UNITED STATES OF AMERICA, ²Division Of Cardiology, Department Of Internal Medicine, Baylor University Medical Center, Dallas/UNITED STATES OF AMERICA, ³, Baylor Institute for Immunology Research, Dallas/UNITED STATES OF AMERICA, ⁴Islet Cell Transplant Program, Baylor Regional Transplant Institute, Dallas/UNITED STATES OF AMERICA

Body: Introduction: Islet transplantation is a promising treatment for type 1 diabetic patients; however, there are several hurdles to make islet cell transplantation as the standard therapy. Early graft loss immediately after islet transplantation caused primarily due to inflammation is one of such issues. Recently we and others demonstrated that IL-1 beta played critical role at the onset of juvenile diabetes. In addition, based on collaborative islet transplant registry (CITR) database, TNF-alpha blockage significantly improved clinical outcome of islet transplantation. Therefore, we hypothesized that combined inflammatory blockade using anakinra (IL-1beta blocker) and etanercept (TNF-alpha blocker) will improve the efficacy of islet transplantation.
Methods: Nine clinical grade human pancreata were procured by surgeons who belonged to islet isolation team. Pancreatic ductal preservation was performed using ET-Kyoto solution and oxygen static charged two-layer method was used for transportation of procured pancreata in all cases (Cell Transplantation in press). Islets were isolated using modified Ricordi method. When isolated islet preparation met transplantation criteria based on the Edmonton protocol, we transplanted those islets into type 1 diabetic patients. We used two immunosuppression and anti-inflammatory protocols. The first protocol used daclizumab for induction and sirolimus and tacrolimus for maintenance immunosuppression. Eternacept was administered for anti-inflammation. The second protocol used thymoglobulin for induction and tacrolimus and mycophenolate mofetile for maintenance immunosuppression. Eternacept and anakinra were administered for anti-inflammation. As an assessment of islet transplantation, total amount of insulin requirement and SUITO index were monitored. To assess the efficacy of anti-inflammatory therapy, we performed gene microarray from patients' peripheral blood samples at pre-transplant, post operative day (POD) 1, 2, 4, 7 with the second protocol.
Results: All isolated islet preparations met criteria for clinical transplantation; therefore, the success rate of clinical islet isolation was 100% (9/9). Nine clinical islet transplantations were performed into 6 type 1 diabetic patients. All patients achieved insulin independence; however, the first protocol required two islet infusions and the second protocol required only single infusion. Average SUITO index at one month was significantly higher in the second protocol group (52.0±9.6 vs. 27.6±12, p<0.05). Gene microarray analysis revealed that T cell and cytotoxic cell related genes were substantially suppressed. However, inflammation and neutrophil related genes were significantly activated suggesting that the other inflammatory mechanisms besides TNF-alpha and IL-1 beta may be relevant. Platelet related genes were not activated suggesting that current anti-coagulation protocol might be enough to prevent coagulation related inflammatory reaction.
Conclusion: Combined IL-1beta and TNF-alpha blockage allowed us to achieve insulin-free status with single-donor islet transplantation. However, the other inflammatory mechanisms may still be operative under this protocol.

Disclosure: All authors have declared no conflicts of interest.