Improving Efficacy of Clinical Islet Transplantation with Iodixanol-Based Islet Purification, Thymoglobulin Induction, and Blockage of IL-1β and TNF-α

Abstract

Poor efficacy is one of the issues for clinical islet transplantation. Recently, we demonstrated that pancreatic ductal preservation significantly improved the success rate of islet isolation; however, two transplants were necessary to achieve insulin independence. In this study, we introduced iodixanol-based purification, thymoglobulin induction, and double blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression to improve the efficacy of clinical islet transplantation. Nine clinical-grade human pancreata were procured. Pancreatic ductal preservation was performed using ET-Kyoto solution in all cases. When the isolated islets met the clinical criteria, they were transplanted. We utilized two methods of immunosuppression and antiinflammation. The first protocol prescribed daclizumab for induction, then sirolimus and tacrolimus to maintain immunosuppression. The second protocol used thymoglobulin for induction and tacrolimus and mycophenolate mofetil to maintain immunosuppression. Eternacept and anakinra were administered as anti-inflammatory drugs. The total amount of insulin required, HbA1c, and the SUITO index were determined to analyze and compare the results of transplantation. All isolated islet preparations (9/9) met the criteria for clinical transplantation, and they were transplanted into six type 1 diabetic patients. All patients achieved insulin independence with normal HbA1c levels; however, the first protocol required two islet infusions (N = 3) and the second protocol only required a single infusion (N = 3). The average SUITO index, at 1 month after a single-donor islet transplantation, was significantly higher in the second protocol (49.6 ± 8.3 vs. 19.3 ± 6.3, p < 0.05). Pancreatic ductal preservation, iodixanol-based purification combined with thymoglobulin induction, and blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression dramatically improved the efficacy of clinical islet transplantations. This protocol enabled us to perform successful single-donor islet transplantations. Further large-scale studies are necessary to confirm these results and clarify the mechanism of each component.

Glycemic Control in Simultaneous Islet-Kidney Versus Pancreas-Kidney Transplantation in Type 1 Diabetes: A Prospective 13-Year Follow-up

“…Prednisone was used in pancreas transplant recipients, but since it could be tapered off in most patients during the first 2-3 years of follow-up or at least could be reduced to low dosages, a relevant impact on glycemic control is unlikely. Published data on induction therapy suggest that induction therapy with thymoglobulin is superior compared with other options (17,18). In our cohort, thymoglobulin induction therapy was only started in 2012; therefore, protocol changes in induction therapy were not influencing long-term outcome.…”

“…Sirolimus was later changed to mycophenolate mofetil because of the high rate of side effects reported for sirolimus (8). Induction therapy was performed initially with daclizumab (Roche Pharma), and after 2012 with thymoglobulin (Sanofi) (18) or basiliximab (Novartis Pharma) for retransplantation.…”

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

“…Recent clinical studies in islet transplantation have used etanercept, a soluble receptor antagonist to TNF-α, alone [47] or in combination with anakinra (a soluble receptor antagonist to IL-1β [19]), to improve islet engraftment using marginal mass islet transplants. The improved outcome of clinical transplants with the combined use of etanercept and anakinra were further corroborated in marginal mass human islet transplants in immunodeficient mice [48].…”

“…Human islet isolation Human-research-grade pancreases were used for isolating islets using methods described previously [19][20][21]. Human islets used in this study were handpicked to greater than 95% purity.…”

Beta Cell Replacement Therapy

“…Immunosuppression after islet transplantation is comprised of two phases namely induction and maintenance therapies. The induction phase is characterized by anti-inflammatory drugs and monoclonal or polyclonal antibodies that deplete immune cells (anti-CD3 and anti-thymocyte globulin) or prevent T-cell activation (anti-IL-2 receptor) (Stock & Bluestone, 2004;Matsumoto et al, 2011). The maintenance drug regimen is focused on suppression of T-cells by various strategies including calcineurin inhibitors such as tacrolimus, and cyclosporine.…”