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Transplantation of Human Islets Without Immunosuppression

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Transplantation of Human Islets Without Immunosuppression Transplantation of human islets without immunosuppression Barbara Ludwiga,b,1, Andreas Reichela,b,1, Anja Steffena,b, Baruch Zimermanc, Andrew V. Schallyd,e,2, Norman L. Blockd,e, Clark K. Coltonf, Stefan Ludwigg, Stephan Kerstingb,g, Ezio Bonifacioh, Michele Solimenab,i, Zohar Gendlerc, Avi Rotemc, Uriel Barkaic, and Stefan R. Bornsteina,b,j aDepartment of Medicine III and gDepartment of Visceral, Thorax, and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany; bCentre for Diabetes Research, Paul Langerhans Institute Dresden, D-01307 Dresden, Germany; cBeta-O2 Technologies, Petach Tikva 49511, Israel; dDivisions of Endocrinology and Hematology–Oncology, Departments of Pathology and Medicine, University of Miami Miller School of Medicine, Miami, FL 33136; eVeterans Administration Medical Center, Miami, FL 33125; fDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; hCenter for Regenerative Therapies Dresden, Technische Universität Dresden, D-01307 Dresden, Germany; iMax Planck Institute of Molecular Cell Biology and Genetics, D-01307 Dresden, Germany; and jDepartment of Endocrinology and Diabetes, King’s College, London SE5 9RJ, England Contributed by Andrew V. Schally, September 20, 2013 (sent for review August 15, 2013) Transplantation of pancreatic islets is emerging as a successful (7–9) the method was then applied to allogeneic human islet treatment for type-1 diabetes. Its current stringent restriction to transplantation in an individual treatment approach in a patient patients with critical metabolic lability is justified by the long-term with long-term type-1 diabetes. The objective of this study was to need for immunosuppression and a persistent shortage of donor determine whether the islet allograft could survive over a pro- organs. We developed an oxygenated chamber system composed longed follow-up period, without any immunosuppressive ther- of immune-isolating alginate and polymembrane covers that allows apy, and could maintain glucose responsiveness. Furthermore, for survival and function of islets without immunosuppression. A biocompatibility of the macrocapsule and the practicability of the patient with type-1 diabetes received a transplanted chamber and oxygen refilling procedure in daily life were evaluated. was followed for 10 mo. Persistent graft function in this chamber system was demonstrated, with regulated insulin secretion and Results preservation of islet morphology and function without any immu- Type-1 Diabetes C Peptide-Negative Patient. We studied a 63-y-old nosuppressive therapy. This approach may allow for future wide- male patient [weight 74 kg, height 1.75 m, body mass index spread application of cell-based therapies. (BMI) 24.5 kg/m2] with a history of type-1 diabetes for 54 y. He has been seen regularly in our outpatient diabetes clinic for more β-cell replacement | immune barrier | oxygenation than 20 y and treated by continuous insulin infusion therapy for 20 y. Despite long-standing autoimmune diabetes he shows no he transplantation of isolated islets of Langerhans has evolved severe secondary diabetes complications, although his metabolic Tinto a successful method to restore endogenous insulin se- lability has increased over the last several years. Overall glycemic cretion and stabilize glycemic control without the risk of hypo- control was acceptable with an average hemoglobin A1c of 7.4% glycemia (1, 2). However, due to persistent lack of human donor and an average daily insulin requirement of 52 international pancreata and the requirement of chronic immune suppression to units (IU)/d. Before enrollment, an i.v. glucose tolerance test prevent graft rejection through allo- and autoimmunity, the in- (ivGTT) was performed to verify complete insulin deficiency dication for islet transplantation is restricted to patients with (nondetectable basal or stimulated C peptide). Before trans- complete insulin deficiency, critical metabolic lability, and re- peated severe hypoglycemia despite optimal diabetes management plant, the patient had insulin antibodies (10.7 IU/mL) and, as is and compliance (3). Furthermore, progressive loss of islet function fi over time due to chronic hypoxia and inflammatory processes at Signi cance the intraportal transplantation site remain additional unresolved challenges in islet transplantation (4, 5). Diabetes mellitus type 1 is an autoimmune disease that results When islets are immune-isolated, the lack of oxygen impairs in irreversible destruction of insulin-producing beta cells. Sub- the survival and long-term function of the cells. Experimental stantial advances have been made in beta cell replacement approaches to overcome this impediment have involved the therapies over the last decades. However, lack of eligible donor implantation of hypoxia-resistant islets, stimulation and sprout- organs and the need for chronic immunosuppression to pre- ing of vessels, and the use of islets designed to contain an in- vent rejection critically limit a widespread application of these tracellular oxygen carrier as well as local oxygen production by strategies. In this paper we present the clinical success of using electrochemical processes or photosynthesis (6). However, so a bioartificial pancreas for the transplantation of insulin- far, none of these methods have been capable of guaranteeing producing islets without affecting the immune system. In a an adequate physiological oxygen concentration or to allow, at patient with long-standing type-1 diabetes we could demon- the same time, an adequate immunoprotective environment. To strate persistent graft function and regulated insulin secretion overcome these major obstacles, we have developed a strategy without the need for immune-modulating medication. This for islet macroencapsulation that provides sufficient immune strategy opens up avenues for more widespread and safe ap- isolation and permits endogenously regulated islet graft function. plication of various cell-based therapies. Here we demonstrate a system that allows a controlled oxygen supply to the islet graft by means of an integrated oxygen res- Author contributions: B.L., A. Reichel, A.S., B.Z., C.K.C., S.L., S.K., E.B., M.S., Z.G., A. Rotem, U.B., and S.R.B. designed research; B.L., A. Reichel, A.S., B.Z., C.K.C., S.L., S.K., E.B., M.S., ervoir that can be refilled regularly and can maintain oxygen A. Rotem, U.B., and S.R.B. performed research; B.L., A. Reichel, A.S., B.Z., A.V.S., N.L.B., E.B., pressure. Earlier we demonstrated that a sufficient supply of M.S., Z.G., A. Rotem, U.B., and S.R.B. analyzed data; and B.L., A. Reichel, A.S., B.Z., A.V.S., oxygen for maintaining optimal islet function can simultaneously N.L.B., E.B., M.S., Z.G., A. Rotem, U.B., and S.R.B. wrote the paper. ensure functional potency and immunoprotective characteristics The authors declare no conflict of interest. of the device. After application of this bioartificial pancreas 1B.L. and A. Reichel contributed equally to this work. system in allogeneic and xenogeneic preclinical diabetes models 2To whom correspondence should be addressed. E-mail: [email protected]. 19054–19058 | PNAS | November 19, 2013 | vol. 110 | no. 47 www.pnas.org/cgi/doi/10.1073/pnas.1317561110 Downloaded by guest on September 27, 2021 often seen in patients with long-term type-1 diabetes, was neg- Evaluation of in Vivo Graft Function. Graft function was evaluated ative for autoantibodies to glutamate decarboxylase 65, islet cell– by frequent blood glucose measurements, determination of sys- antigen 2, and islet cell antibodies. Luminex-based measure- temic basal and stimulated C peptide (ivGTT), and local stim- ments of donor-specific antibodies (anti-HLA class I and II) were ulation of hormone release from the encapsulated islet graft undetectable. Peripheral blood memory T cells did not show following glucose instillation (Fig. 2). a proliferative response to the islet antigens, glutamic acid decar- We demonstrated persistent graft function throughout the boxylase 65, or to proinsulin. follow-up period of 10 mo by detection of positive basal C peptide (0.04 ± 0.03 nmol/L at 1, 3, 6, and 9 mo posttransplantation). Transplantation Procedure. The transplantation of the macro- However, the basal hormone levels were at very low concen- chamber containing the islet graft was performed under general trations, and during i.v. glucose stimulation (0.3 g/kg body weight anesthesia. The preperitoneal pocket for the chamber was bluntly over a 2-min period), C peptide increased to a maximum of 0.8 ± dissected through a 10-cm midline abdominal incision; one ad- 0.02 nmol/L. These hormone levels are below the physiologic ditional small abdominal incision was made close by for implan- range of stimulated C-peptide secretion but provide direct evi- tation of the oxygen ports (Fig. 1B). The chamber and the port dence of successful graft function (Fig. 2A). system were connected via s.c. tunnelled polyurethane tubes. The patient received antibiotic prophylaxis; no immunosuppressive or Local Assessment of Graft Function Following High-Glucose Challenge. anti-inflammatory agents were administered. To assess the effective capacity of the encapsulated islet graft, Surgery was straightforward and without complications. Sys- a high-glucose solution (15 mmol/L) was instilled locally around temic pain treatment was only required for the first 2 days fol- the chamber system under ultrasound control. Samples were taken lowing implantation. As detected by ultrasound, local edema for up to 180 min and assayed for C peptide, insulin, and pro- around the device developed on day 3 and resolved only after insulin. A rapid insulin secretion response was observed, dem- 2 wk. The patient did not report any discomfort due to the onstrating proof of islet viability via responsiveness to glucose implanted chamber. No effect of the foreign material was per- (Fig. 2B). ceptible in daily life, and there was no impact on mobility. For This direct evidence of allogeneic graft function was accom- sufficient oxygen supply despite a nonvascularized and therefore panied by a persistent lowering in hemoglobin A1c (Fig.
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