Transplantation of human islets without immunosuppression

Abstract

Transplantation of pancreatic islets is emerging as a successful treatment for type-1 diabetes. Its current stringent restriction to patients with critical metabolic lability is justified by the long-term need for immunosuppression and a persistent shortage of donor organs. We developed an oxygenated chamber system composed of immune-isolating alginate and polymembrane covers that allows for survival and function of islets without immunosuppression. A patient with type-1 diabetes received a transplanted chamber and was followed for 10 mo. Persistent graft function in this chamber system was demonstrated, with regulated insulin secretion and preservation of islet morphology and function without any immunosuppressive therapy. This approach may allow for future widespread application of cell-based therapies.β-cell replacement | immune barrier | oxygenation T he transplantation of isolated islets of Langerhans has evolved into a successful method to restore endogenous insulin secretion and stabilize glycemic control without the risk of hypoglycemia (1, 2). However, due to persistent lack of human donor pancreata and the requirement of chronic immune suppression to prevent graft rejection through allo-and autoimmunity, the indication for islet transplantation is restricted to patients with complete insulin deficiency, critical metabolic lability, and repeated severe hypoglycemia despite optimal diabetes management and compliance (3). Furthermore, progressive loss of islet function over time due to chronic hypoxia and inflammatory processes at the intraportal transplantation site remain additional unresolved challenges in islet transplantation (4, 5).When islets are immune-isolated, the lack of oxygen impairs the survival and long-term function of the cells. Experimental approaches to overcome this impediment have involved the implantation of hypoxia-resistant islets, stimulation and sprouting of vessels, and the use of islets designed to contain an intracellular oxygen carrier as well as local oxygen production by electrochemical processes or photosynthesis (6). However, so far, none of these methods have been capable of guaranteeing an adequate physiological oxygen concentration or to allow, at the same time, an adequate immunoprotective environment. To overcome these major obstacles, we have developed a strategy for islet macroencapsulation that provides sufficient immune isolation and permits endogenously regulated islet graft function. Here we demonstrate a system that allows a controlled oxygen supply to the islet graft by means of an integrated oxygen reservoir that can be refilled regularly and can maintain oxygen pressure. Earlier we demonstrated that a sufficient supply of oxygen for maintaining optimal islet function can simultaneously ensure functional potency and immunoprotective characteristics of the device. After application of this bioartificial pancreas system in allogeneic and xenogeneic preclinical diabetes models (7-9) the method was then applied to allogeneic human islet transplantation in an ind...

Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus

“…These observations are in agreement with findings reported previously in a patient in whom the βAir device with human islets was implanted in the pre‐peritoneal space, a site considered to be superior when compared with subcutaneous implantation 7. Even so, the kinetics of glucose‐stimulated insulin release during an intravenous glucose tolerance test showed a significant delay in secreted C‐peptide over a 4‐hour period also at the pre‐peritoneal space 7. Given the physiological differences between different tissue compartments, especially regarding vascularity, the most advantageous site for transplantation of macroencapsulation devices remains to be determined.…”

“…Diffusion of larger molecules, for example, insulin (5800 Da) and IAPP (3900 Da) secreted from the encapsulated islets, would be expected to be even more delayed. These observations are in agreement with findings reported previously in a patient in whom the βAir device with human islets was implanted in the pre‐peritoneal space, a site considered to be superior when compared with subcutaneous implantation 7. Even so, the kinetics of glucose‐stimulated insulin release during an intravenous glucose tolerance test showed a significant delay in secreted C‐peptide over a 4‐hour period also at the pre‐peritoneal space 7.…”

“…The βAir device partly solves the problem with oxygen delivery, but requires daily refilling of the oxygen chamber through one of the 2 subcutaneous Port‐A‐Cath ports 7. Other than for the initial technical problems with rotation of the ports encountered in patient 2, there were no reports of missed or failed oxygen refillings during the course of study, which indicated that this strategy is feasible.…”

“…To solve this matter, the βAir device with an incorporated refillable oxygen tank was developed and successfully tested in small and large animal models 4, 5, 6. The present clinical phase 1 study was conducted to evaluate the safety of implanting the βAir device7 containing isolated allogeneic human islets in patients with type 1 diabetes. The device was implanted subcutaneously in subjects with well‐controlled and uncomplicated type 1 diabetes.…”

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…To let the cells survive until well-vascularized, encapsulation devices have been produced with built-in oxygen supply. 37 Depending on the encapsulation device, reprogrammed cells can be transplanted under the skin, into the peritoneal cavity, the omental pocket, or intravenously. 38 Although few phase I and IIa clinical trials are still ongoing or have been completed, metabolic control and survival time of transplants are still not quite satisfactory.…”