Immuno-Isolation of Pancreatic Islet Allografts Using Pegylated Nanotherapy Leads to Long-Term Normoglycemia in Full MHC Mismatch Recipient Mice

Abstract

Two major hurdles need to be surmounted for cell therapy for diabetes: (i) allo-immune rejection of grafted pancreatic islets, or stem/precursor cell-derived insulin-secreting cells; and (ii) continuing auto-immunity against the diabetogenic endogenous target antigen. Nanotherapeutics offer a novel approach to overcome these problems and here we ask if creation of “stealth” islets encapsulated within a thin cage of pegylated material of 100–200 nanometers thick provides a viable option for islet transplantation. The aims of this study were to test islet viability and functionality following encapsulation within the pegylated cage, and functional efficacy in vivo in terms of graft-derived control of normoglycemia in diabetic mice. We first demonstrated that pegylation of the islet surface, plus or minus nanoparticles, improved long-term islet viability in vitro compared to non-pegylated (naked) control islets. Moreover, pegylation of the islets with nanoparticles was compatible with glucose-stimulated insulin secretion and insulin biogenesis. We next looked for functionality of the created “stealth” DBA/2 (H-2d) islets in vivo by comparing glycemic profiles across 4 groups of streptozotozin-induced diabetic C57BL/6 (H-2b) recipients of (i) naked islets; (ii) pegylated islets; (iii) pegylated islets with nanoparticles (empty); and (iv) pegylated islets with nanoparticles loaded with a cargo of leukemia inhibitory factor (LIF), a factor both promotes adaptive immune tolerance and regulates pancreatic β cell mass. Without any other treatment, normoglycemia was lost after 17 d (+/−7.5 d) in control group. In striking contrast, recipients in groups (ii), (iii), and (iv) showed long-term (>100 d) normoglycemia involving 30%; 43%, and 57% of the recipients in each respective group. In conclusion, construction of “stealth” islets by pegylation-based nanotherapeutics not only supports islet structure and function, but also effectively isolates the islets from immune-mediated destruction. The added value of nanoparticles to deliver immune modulators plus growth factors such as LIF expands the potential of this novel therapeutic approach to cell therapy for diabetes.

The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model

“…While islet PEGylation as a singular approach has not shown substantial promise, selected studies have demonstrated a synergistic impact when combined with low-dose or local immunosuppression [29–31]. In this study, we sought to explore the impact of a targeted and short-course immune intervention used in combination with islet PEGylation.…”

Collagen IV-Modified Scaffolds Improve Islet Survival and Function and Reduce Time to Euglycemia

“…4 In particular, the shortage of donors and the necessity for multiple rounds of islet infusion limit the widespread use of islet transplantation and compels the development of strategies to improve the survival and function of transplanted islets. [5][6][7][8][9][10] Tissue-engineering scaffolds have been employed as a means to support the function of transplanted islets; however, to date, the focus of using biomaterials for islet transplantation has been largely on immunoisolation of islets to prevent rejection, 11 which has faced challenges related to the fibrotic response to the implant. Abrogating the allo-and autoimmune responses of islet transplantation remains an important problem, but the need for multiple islet infusions and islet failure over time also relates, in part, to the current approach for islet transplantation, intrahepatic infusion.…”

Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

“…In addition, when the devices were removed after 400 days, viable islets were recovered with a small percentage of necrotic cells [14]. Aside from agarose, polyethylene glycol-poly lactic-co-glycolic acid (PEG-PLGA) has been used to encapsulate 500-600 IEq islets for syngeneic transplant into streptozotocin (STZ) induced diabetic BALB/c mice, where over half of the recipients achieved normal glucose levels for up to 100 days [15].…”