Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model

Abstract

Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti‐inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long‐chain poly(ethylene glycol) (PEG) to mitigate detrimental host‐implant interactions. The effect of PEGylation on islet engraftment and long‐term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti‐thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC‐matched recipients and received MHC‐disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c‐peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.

Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing

“…Diabetes was induced with 100 mg/kg IV streptozotocin (Zanosar, TEVA, Irvine, CA) as previously described 38 and was confirmed 2–4 weeks post‐treatment and defined as fasting c‐peptide <0.3 and stimulated <0.5 ng/ml. Details in Supporting Information.…”

“…Islets with or without MSC were transplanted into the liver on POD 0. Figure 1B summarizes the timing and route of administration of MSC: no MSC (islets alone on POD 0 [data from one control, H10C21, was included in a recent publication 38 ]); POD 0 (islets + 1 × 10 6 MSC/kg on POD 0); POD 0 + IV (islets + 1 × 10 6 MSC/kg on POD 0 and 2 × 10 6 IV MSC/kg on POD 5, 11, 18, and 28); and delayed IV (islets alone on POD 0 and 2 × 10 6 IV MSC/kg on POD 1, 5, 11, 18, and 28). FK506 and rapamycin trough levels were monitored weekly.…”

“…Immunophenotyping of whole blood, peripheral blood mononuclear cells from CFSE mixed lymphocyte reaction (MLR), and MSC, as well as alloantibody assessment, were undertaken via immunofluorescent staining and flow cytometric analysis as previously described. 38 All flow cytometry samples included a Live/ Dead Fixable Near-IR Dead Cell Stain (Molecular Probes, Grand Island, NY) for viability assessment and were run on a Becton Dickinson LSR II cytometer and analyzed using Kaluza software (version 1.5a, Beckman Coulter). Full details are in Supporting Information.…”

Development of Advanced Cell-Based Therapy by Regulating Cell–Cell Interactions

“…Previous research shows that polymer modification of islets resulted in higher survival after transplantation, as these islets could avoid immune cells. 70) Cell surface modification can result in novel cell functions and regulate cell-cell interaction between transplanted cells. This strategy can be developed into a useful tool for the advanced cell-based therapy.…”

PEGDA microencapsulated allogeneic islets reverse canine diabetes without immunosuppression

“…PEGDA has advantages because the precursors are widely available and inexpensive with appropriate diffusion characteristics [ 21 , 22 ]. In different formulations, the base chemistry (PEG) has been used to protect islets from immune rejection in multiple studies [ 23 – 25 ]. Unfortunately, because of the slow gelation properties of PEGDA [ 26 ], it could not be formulated as microspheres except when produced using emulsion techniques, which can be harmful to cells.…”