New Strategies for Clinical Islet Transplantation (original) (raw)
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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.
Islet transplantation: immunological perspectives
Current Opinion in Immunology, 2003
Clinical trials of islet transplantation are showing remarkable success, but they require administration of chronic immunosuppression, and are underscoring the large gap that exists between the number of human donors available and the number of patients that could benefit from the procedure. Recent progress has been made in the definition of key immunological mechanisms that are involved in determining islet transplant outcome. Clinical and preclinical studies, and studies in small animal model systems, will all eventually contribute to the definition of efficient and safe protocols for islet transplantation. If the use of xenografts is successful, it might represent a solution to the shortage of human organs.
Transplantation Proceedings, 1998
A UNIQUE and natural approach to immunoisolation of islet grafts was explored by investigating different immunoprivileged sites of the body: the brain, 1,2 the testis, 3,4 and the renal subcapsular space. 5,6 For the intraabdominally placed testis, immunologic privilege has been, undoubtfully, demonstrated 3,4 and attributed to locally produced factors that inhibit the immune response. 7-9 However, the clinical inapplicability and the possible malignant transformation of the germ cells stand as major drawbacks of grafting the islets in such an unconventional organ site. The data about renal subcapsular space are contradictory. Whereas some investigators reported failure of islet allografts to function and survive in the renal subcapsular space, 3,7 others 5,6 demonstrated a remarkable success of islet allografting in this place. We investigated the engraftment, survival, and metabolic function of murine islet allografts when placed in two organ sites, the intraabdominally placed testis and the renal subcapsular space, without immunosuppression.
Islet transplantation in the twenty-first century
Immunologic Research - IMMUNOL RES, 2002
Isolated islet transplantation is poised for clinical application to treat insulin-dependent diabetes. Unlike exogenous insulin therapy, islet transplantation has promise for preventing and/or reversing the dismal secondary complications of diabetes. Islet transplants are arguably the most unique type of allografts, and we discuss their properties, limitations, and potential in this overview. The induction of immunologic tolerance to allow islet grafts to endure and prevail, without the hardship of chronic immunosuppressive therapy, is a major goal in this field. In this context, we discussour successful results in preclinical models of primate allogeneic and xenogeneic islet graft tolerance.
Transplantation, 2008
Islet graft survival inside macroencapsulation devices is suboptimal. We hypothesized that induction of neovascularization by preimplantation of devices would improve the physiological conditions, thereby lowering the number of islets required for cure. Several rat islets were transplanted to TheraCyte immunoprotective devices implanted subcutaneously in diabetic athymic mice. Cure rates in the groups with preimplanted devices were significantly better than in those with freshly implanted devices (375 islets: 8/8 vs. 1/6, Pϭ0.003; 125 islets: 6/6 vs. 0/7, Pϭ0.001). Morphometric evaluations of the 125 islet groups showed higher fractional and absolute volumes of endocrine tissue in the group with preimplanted devices (PϽ0.001 and Pϭ0.035, respectively). In the following dose titration study, using preimplanted devices, as low as 50 islets cured diabetic mice (100% cure, nϭ6). We conclude that preimplantation significantly lowers the curative dose of macroencapsulated islets to levels resembling those of free islets transplanted under the renal capsule.
Purity of islet preparations and 5-year metabolic outcome of allogenic islet transplantation
American Journal of Transplantation, 2017
Allogenic islet transplantation (IT) is currently recognized as a key strategy for treatment of brittle type 1 diabetes (T1D). 1 The original Edmonton protocol 2 combines a steroid-free immunosuppression protocol with 2 to 3 injections of islets prepared from deceased donor pancreata 3 over a 3-month period. The preparations are generally characterized by the number and total volume of islets, their viability, and their purity, which is expressed as the proportion of endocrine (ie, dithizone stained) relative to the exocrine tissue in the final preparation. 4 Numerous factors of islet transplantation success have been identified including primary graft function, which reflects the overall quality of the preparation. 5 The purity of islet preparation is also considered as a critical factor, which influences the efficacy and safety of IT. 6 Successful transplantation of unpurified islets prepared from a single donor has been reported, however. 7 High content of pancreatic ductal cells (ie, lower purity) has been also associated with higher acute insulin response (AIR) 1 year after allogenic IT. 8 This could be attributed to secondary neogenesis of beta cells arising from ductal cells after transplantation. 9,10 Notably, human ductal cells were recently shown to