Immuno-Isolation Strategies for Islet Transplantation into Rodent and Non-Human Primate Models
thesisposted on 18.02.2018 by Matthew A. Bochenek
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
Human pancreatic islet transplantation into the liver of patients with Type 1 Diabetes Mellitus can restore physiological glycemic control. However, this therapy requires immunosuppression with potential health risks. To universally apply this therapy, immuno-isolation strategies have been explored to protect islets from rejection without immunosuppression. Achieving proper oxygenation of islets is a leading obstacle to these technologies. Properly functioning islets respire extensively, and immune-isolated islets must rely entirely on oxygen diffusion. Also, immune-isolation materials can become fibrosed, which hampers oxygenation. Immune-isolated islets are commonly transplanted into the peritoneal cavity, despite having low oxygen availability. Skeletal muscle tissue may represent an alternative transplantation site due to the higher oxygen levels. Rat muscles were transplanted with empty, isogeneic, and allogeneic islets encapsulated in alginate. Skeletal muscle tissue was found to tolerate the alginate material and support viable isogeneic islets for 8 weeks. Allogeneic islets were found to be fibrosed and not viable after 8 weeks. MIT recently showed that fibrosis of alginate spheres is dependent on size, and medium 0.5 mm spheres induce more fibrosis compared to large 1.5 mm spheres (Veiseh, 2015). We are investigating the size effects on islet functionality. Insulin secretory kinetics were measured for naked and encapsulated islets at the two sizes. A short delay in insulin secretion was found for encapsulated islets regardless of size; however, overall bulk insulin kinetics were similar among the three groups. In vivo assays showed large encapsulated NHP islets efficiently cured both immune incompetent and competent mouse models. Also, 14 day short-term culture of large encapsulated islets does not reduce in vivo functionality. MIT also developed a series of chemically modified alginates that demonstrate fibrosis resistive properties. The protective capacities of these materials were investigated using a cynomolgus NHP allogeneic transplant model. The RZA15 variation remained free of fibrosis and protected viable, glucose responsive islets 4 weeks post-transplantation. Lastly, we developed a novel encapsulator for the continuous production of spherical hydrogels with controlled size and gelation time. This encapsulator may be suited to encapsulate islets for clinical transplantation in the future.