Strategies to improve macroencapsulated islet graft survival
Year: 2007
Type: dissertation
Abstract: Chronic immunosuppressive therapy may have severe side-effects. In cell\ntransplantation, the graft can be encapsulated within a membrane chamber,\nproviding a physical barrier against the immune system. The cell graft\nthen becomes dependent on the diffusion of nutrients and oxygen from the\nsurrounding microcirculation. A major drawback has been the formation of\navascular fibrotic tissue around the chamber. The immunoprotective device\nstudied (TheraCyte ) has an outer membrane inducing neovascularization.\nHowever, major parts of the encapsulated graft are still lost soon after\ntransplantation, probably because of relative hypoxia and malnutrition.\nThe overall aim of this thesis was to assess various strategies to\nimprove islet graft survival in the device, using rodent models.\n\nThe purpose of the first paper was to improve the method for histological\nevaluation of the vascularization around the device. Vascular profiles\nwithin various distances from the membrane surface were counted at\ndifferent times and then correlated with glucose kinetics. We found that\nthe vascular profiles within 100 ìm had the highest correlations with\nglucose kinetics and concluded that vessels within this distance are\nimportant for the exchange of small molecules between the circulation and\nthe device s lumen. Therefore, we recommend that 100 ìm should be used in\nhistological evaluations of the membrane vascularization.\n\nIn the second paper we hypothesized that preimplantation of the device\nshould improve encapsulated islet graft survival. Previous studies have\nindicated that it takes up to 3 months for recovery of the\nmicrocirculation after membrane implantation. Therefore, we implanted\nempty devices and transplanted islets 3 months later in these chambers.\nThis approach significantly improved the cure rates of diabetic animals,\nand the islet dose required for cure was reduced by about 10 times.\nMorphometry evaluations confirmed increased graft survival in\npreimplanted devices.\n\nThe third paper aimed at evaluating the effects of exendin-4 treatment on\nthe metabolic outcome after islet transplantation. Exendin-4 inhibits\nislet apoptosis, stimulates islet differentiation and regeneration and\nhas beneficial effects on peripheral tissues. We found that exendin-4\ntreatment significantly improved the metabolic outcome after free islet\ntransplantation to the renal subcapsular site. The benefit lasted longer\nthan the treatment, suggesting that exendin-4 had long-standing effects\non the islet graft. This substance seems to be an interesting new\napproach to improve the survival also of encapsulated islet grafts.\n\nIn the last paper we evaluated the risk of recipient sensitization using\nmacroencapsulated islets. A heterotopic heart graft was transplanted one\nmonth after free or encapsulated islet transplantation. The\ntime-to-rejection was significantly shorter in the free islet group,\nwhile it did not differ between encapsulated islet graft recipients and\nnaive animals. We therefore conclude that the device protects against\nsensitization, at least during the first month after transplantation.\n\nToday, side-effects of the immunosuppressive therapy are one of the main\nlimiting factors for the use of islet transplantation. If\nimmunoprotection could be achieved by encapsulation of the islet graft,\nit should be possible to widen the indications. This thesis describes\npromising strategies to improve the survival of macroencapsulated islet\ngrafts, which might contribute to make macroencapsulation a clinical\nreality.
Source: Figshare
Author: Anne Sörenby
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2107497611