Porcine Islet Xenotransplantation for the Treatment of Type 1 Diabetes

Porcine Islet Xenotransplantation for the Treatment of Type 1 Diabetes 481 Porcine islets as a potential solution to the shortage of human isletsPigs have been the focus of islet xenotransplantation for a number of reasons -they are inexpensive, readily available, breed quickly and produce large litters.Their islets display many morphologic and structural similarities to human islets, and respond to glucose levels in the same physiologic range (Cardona et al., 2007).Porcine insulin differs from human insulin by only one amino acid, and as such has been used clinically to treat patients with type 1 diabetes for many years (Dufrane & Gianello, 2009).Pig donors have many advantages with respect to transplantation: i) they are not exposed to compromising conditions such as comorbidity, brain death and cold ischemic injury as many deceased human donors are; ii) they may be housed in pathogen-free facilities which may allow for an on-demand source of islets with limited risk of pathogen transmission; iii) they may be genetically modified in order to change the expression of proteins, which may ultimately allow for the procurement of less immunogenic tissue (Hering & Walawalker, 2009;Ricordi et al., 1990;Korbutt et al., 1996). The optimal age of the donor pigThree main age groups of donor pigs have been investigated to date -adult, fetal, and neonatal -however, the optimal age is still being debated.Adult pigs are a potential source of tissue, as the isolated islets function well both in vitro and in vivo immediately upon isolation, and the yield is substantial.Ricordi et al. demonstrated that approximately 255,000 islets could be isolated per adult pig pancreas, using a technique modified from the human islet isolation procedure.The final preparation was 85-90% pure and reversed hyperglycemia in nude mice (Ricordi et al., 1990).Adult pig islets, however, do have their disadvantages.They are difficult to isolate and maintain in culture, are fragile, and are more susceptible to ischemic and hypoxic damage than neonatal porcine islets.In addition, they lack growth potential (Smith & Mandel, 2000), which limits their ability to recover from any damage upon transplantation.Adult islets may also be relatively more immunogenic upon transplantation, which may only increase the need for immunosuppression (Bloch et al., 1999).In order to be suitable for clinical transplantation, the pigs must be maintained in a pathogen-free environment until they are of an appropriate age for donation.This can be very costly and logistically very difficult, which can limit the applicability of adult pigs as islet donors.The processing of fetal pig pancreata yield porcine fetal islet-like clusters (FICC), an immature group of cells that is capable of producing insulin.In 1988, a simplified procedure for the procurement of FICC was developed by Korsgren et al., which is a simple procedure that does not require the ductal infusion of collagenase or ficoll gradient separation of islets that is seen in adult islet isolation.Media changes every second day purifies the islets, but the functional ability of the FICC is still poor due to their immaturity.They can be maintained in culture for up to 30 days, and are capable of proliferating, however, in vivo reversal of hyperglycemia in animals can take months (Korsgren et al., 1991).In addition, the yield of FICC per pancreas is low, and an estimated 100 porcine donors would be necessary to transplant one 70-kg patient (Korsgren et al., 1991).A functionally mature islet source with the isolation ease seen in fetal pig donors can be found in neonatal porcine donors.Korbutt et al. developed a protocol in 1996 for the isolation of neonatal porcine islets (NPI), which is easy to perform, with a consistent yield of approximately 50,000 islets per pancreas.The preparation consists of 35% fully

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