Polymeric Nano-Shielded Pancreatic Islets for Prevention of Immune Reactions against Transplanted Graft

Abstract

The advances in exogenous insulin therapy has been able to improve the lifestyle of Type-1 diabetic (T1DM) patients, but no formulation till date is yet to mimic the nyctohemeral rhythms of this hormone. In spite of all engineering progresses, a mechanical replacement of pancreatic β cell is still out of reach. Pancreatic islet or the whole pancreas transplantation are the only realistic approach towards finding the 'cure' of the disease. In pancreas, only 1-1.5% cells are insulin secreting

therefore, islet transplantation arises as a more realistic alternative. After the introduction of 'Edmonton protocol' in 2000, clinical islet transplantation is now considered as one of the safest and least invasive transplantation procedures. The protocol proposed several modifications to the existing procedures, such as transplantation of freshly isolated islets from more than one donor pancreas, and use of a steroid-free immunosuppressive drug protocol, which increased the initial success rate significantly. A five-year follow-up study confirmed improved glycemic control in a significant number of recipients, however, only 7.5% of them have attained insulin independence. Therefore, continuous researches have been carried out to improve the protocol in the preservation of the efficacy of the transplanted islets. In order to have an improved outcome and availability of this technology we still have to tackle with the problems related with donor shortage and immunogenicity. Porcine islet xenotransplantation has arisen as a potential alternative source of clinical islet transplantation due to its structural and anatomical similarities with human islets. Moreover, to get around immunogenicity, islet nano-shielding with biocompatible polymers has offered a great promise to increase survival time in combination with immunosuppressive drugs. In this thesis, islet nano-shielding was performed with polymers, such as gelatin, polyethylene glycol (PEG), heparin (Hep), and tannic acid (TA)

and validated in different animal models. Nano-shielding with an artificial extracellular matrix (A. ECM) based material stabilized inherently fragile porcine islets from dissociation after isolation, when PEG was incorporated into the shielding composition, the immunogenicity was significantly reduced. PEG/PEG-Hep abrogated plasma protein adsorption on the nano-shielded surfaces, reduced instant blood-mediated inflammatory reactions (IBMIR) and immune cell activation while exerting no cytotoxic effects on the islets. Finally, nano-shielded non-human primate (NHP) islets demonstrated excellent success rate in both allo- and xeno-recipients with less immune infiltration. One of the benefits of employing nano-shielding technology for islet immunoisolation is it restricts the increment of cell size more than a few nanometers, which makes clinical transplantation feasible through the conventional portal vein. Moreover, the nano-shielding has synergistic effects on increasing survival time with an appropriate immunosuppressive drug regimen. We believe this is the cutting-edge technology with immense potential in clinical transplantation at the moment. If applied with the current immunosuppressive drug protocol, clinical islet transplantation would enter into a new dimension.