FasL microgels induce immune acceptance of islet allografts in nonhuman primates

Abstract

Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)–FasL–presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3 + cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in β cell replacement for treating type 1 diabetes.

Defining the chromatin and transcriptional landscape of stem cell-derived islets

“…SC-islets have been generated from patients with diabetes for study of diabetes pathology and consideration as an autologous cell source of diabetes regenerative medicine 12,[71][72][73][74][75][76] . Finally, many materials are being studied to provide immune protection or otherwise benefit islets or SC-islets after transplantation [77][78][79][80][81][82][83][84] .…”

A hydrogel platform for co‐delivery of immunomodulatory proteins for pancreatic islet allografts

“…Within a similar context, delivery of fully mismatched BALB/c islets and SA‐FasL on PEG‐4MAL microgels, with a short course of rapamycin, yielded allograft acceptance and function over 200 days 14 . This same technology was extended to chemically diabetic nonhuman primates, where it induced the acceptance of islet allografts 15 . Despite these compelling results, translation into the clinic may require a scaled‐up course of rapamycin, hence not fully eliminating the need for systemic immunosuppression – albeit a short course and not for the duration of the graft.…”

“…14 This same technology was extended to chemically diabetic nonhuman primates, where it induced the acceptance of islet allografts. 15 Despite these compelling results, translation into the clinic may require a scaled-up course of rapamycin, hence not fully eliminating the need for systemic immunosuppressionalbeit a short course and not for the duration of the graft. dose-dependent manner.…”

“…Onset T1D clinical trials have shown that short‐term restoration of the Treg/Teff balance can temporarily slow down disease progression 13 . Prior work from our group demonstrated that controlling the Treg/Teff balance at the local transplantation site using FasL‐presenting microgels under a 2‐week course of rapamycin treatment achieved long‐term allogeneic islet graft survival in chemically diabetic mice and nonhuman primates 14,15 . Rapamycin was used in conjunction with FasL because of its synergistic effects in inducing apoptosis of alloreactive T cells and generation of Tregs.…”

“…13 Prior work from our group demonstrated that controlling the Treg/Teff balance at the local transplantation site using FasL-presenting microgels under a 2-week course of rapamycin treatment achieved long-term allogeneic islet graft survival in chemically diabetic mice and nonhuman primates. 14,15 Rapamycin was used in conjunction with FasL because of its synergistic effects in inducing apoptosis of alloreactive T cells and generation of Tregs. However, rapamycin increases the number of both Tregs and Teffs at the graft site, 14 suggesting that a more Treg-selective strategy could lead to Treg predominance.…”