The Long Road to Pancreatic Islet Transplantation (original) (raw)
Related papers
Transplantation of human islets without immunosuppression
PNAS, 2013
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 immu-nosuppressive 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 hypo-glycemia (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 in-tracellular 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 individual treatment approach in a patient with long-term type-1 diabetes. The objective of this study was to determine whether the islet allograft could survive over a prolonged follow-up period, without any immunosuppressive therapy , and could maintain glucose responsiveness. Furthermore, biocompatibility of the macrocapsule and the practicability of the oxygen refilling procedure in daily life were evaluated. Results Type-1 Diabetes C Peptide-Negative Patient. We studied a 63-y-old male patient [weight 74 kg, height 1.75 m, body mass index (BMI) 24.5 kg/m 2 ] with a history of type-1 diabetes for 54 y. He has been seen regularly in our outpatient diabetes clinic for more than 20 y and treated by continuous insulin infusion therapy for 20 y. Despite long-standing autoimmune diabetes he shows no severe secondary diabetes complications, although his metabolic lability has increased over the last several years. Overall glycemic control was acceptable with an average hemoglobin A1c of 7.4% and an average daily insulin requirement of 52 international units (IU)/d. Before enrollment, an i.v. glucose tolerance test (ivGTT) was performed to verify complete insulin deficiency (nondetectable basal or stimulated C peptide). Before transplant , the patient had insulin antibodies (10.7 IU/mL) and, as is Significance Diabetes mellitus type 1 is an autoimmune disease that results in irreversible destruction of insulin-producing beta cells. Substantial advances have been made in beta cell replacement therapies over the last decades. However, lack of eligible donor organs and the need for chronic immunosuppression to prevent rejection critically limit a widespread application of these strategies. In this paper we present the clinical success of using a bioartificial pancreas for the transplantation of insulin-producing islets without affecting the immune system. In a patient with long-standing type-1 diabetes we could demonstrate persistent graft function and regulated insulin secretion without the need for immune-modulating medication. This strategy opens up avenues for more widespread and safe application of various cell-based therapies.
Considerations for an Alternative Site of Islet Cell Transplantation
Journal of Diabetes Science and Technology, 2019
Islet cell transplantation has been limited most by poor graft survival. Optimizing the site of transplantation could improve clinical outcomes by minimizing required donor cells, increasing graft integration, and simplifying the transplantation and monitoring process. In this article, we review the history and significant human and animal data for clinically relevant sites, including the liver, spleen, and kidney subcapsule, and identify promising new sites for further research. While the liver was the first studied site and has been used the most in clinical practice, the majority of transplanted islets become necrotic. We review the potential causes for graft death, including the instant blood-mediated inflammatory reaction, exposure to immunosuppressive agents, and low oxygen tension. Significant research exists on alternative sites for islet cell transplantation, suggesting a promising future for patients undergoing pancreatectomy.
Pharmazie, 2010
Emerging biotechnologies, such as the use of biohybrid devices for cellular therapies, are showing increasing therapeutic promise for the treatment of various diseases, including type 1 diabetes mellitus. The functionality of such devices could be greatly enhanced if successful localized immunosuppression regimens could be established, since they would eliminate the many otherwise unavoidable side effects of currently used systemic immunosuppressive therapies. The existence of local immune privilege at some specialized tissues, such as the eye, CNS, or pregnant uterus, supports the feasibility of localized immunomodulation, and such an approach is particularly well-suited for cell transplant therapies where all transplanted tissue is localized within a device. Following the success of syngeneic transplantation in a subcutaneous prevascularized device as a bioartificial pancreas in a rodent model, we now report the first results of exploratory in vivo islet allograft studies in rats ...
Diabetes, 2016
Transplantation of pancreatic islets is a therapeutic option to preserve or restore β-cell function. Our study was aimed at developing a clinically applicable protocol for extra-hepatic transplantation of pancreatic islets. The potency of islets implanted onto the omentum, using an in situ-generated adherent, resorbable plasma-thrombin biologic scaffold, was evaluated in diabetic rat and in a nonhuman primate (NHP) models. Intraomental islet engraftment in the biologic scaffold was confirmed by achievement of improved metabolic function and preservation of islet cytoarchitecture, with reconstitution of rich intra-insular vascular networks in both species. Long-term non-fasting normoglycemia and adequate glucose clearance (tolerance tests) was achieved in both intrahepatic and intraomental sites in rats. Intraomental graft recipients displayed lower levels of serum biomarkers of islet distress (e.g., acute serum insulin) and inflammation (e.g., leptin and α2-macroglobulin). Important...
Acta Diabetologica, 1992
Transplantation of xenogeneic islets in immunoisolating membranes may solve the problems of the availability of human donor organs and long-term immunosuppression. Alginates are widely used for microencapsulation of isolated islets. This study presents data of a new method in which alginate was cross-linked with barium ions. In the perifusion experiment microencapsulated rat islets showed a biphasic insulin release with a short delay of the first phase. During static glucose challenge the insulin release ranged from 40% to 70% compared to free floating controls. In 3 of 11 diabetic mice, transplantation of 800 barium-alginate-bead encapsulated rat islets resulted in a non-fasting normoglycaemia at least up to 70 days. In the same model, transplantation of 3000 encapsulated porcine islets resulted in 6 of 10 recipients in normoglycaemia up to day 70, while 3 animals were still normoglycaemic on day 100. On day 21 after transplantation of encapsulated rat and porcine islets and intraperitoneal glucose tolerance test revealed rapid glucose assimilation in both groups. Histological examination demonstrated well-preserved islets at the end of the experiments. Immunohistological B-cell staining revealed the absence of recruitment of β-cells in the recipient's own pancreas. The barium-alginate microencapsulation method represents a simple one-step method for effective immunoisolated transplantation of large-scale islet preparations.
Transplantation Proceedings, 1997
I SLET TRANSPLANTATION is a potential cure for diabetes mellitus. One major problem remains the necessity of immunosuppression. One experimental strategy to prevent rejection is immunoisolation. Current methods of immunoisolation use artificial materials as barrier devices.' These materials are not completely inert and induce a foreign body and inflammatory reaction. The resulting fibrous tissue overgrowth decreases the diffusion properties. Stimulated macrophages secrete nitric oxide which penetrates the barriers and destroys the encapsulated islets.2 We proposed the encapsulation of Islets of Langerhans with a layer of autologous chondrocytes to prevent immunorecognition and destruction of allogeneic or xenogeneic islets. METHODS Islets of Langerhans were isolated from Lewis rats (200 to 300 g).3 One thousand islets were seeded on a 1 X 1 X 0.06-cm biodegradable, porous polyglycolic acid (PGA) polymer scaffold (density, 40