The Efficacy of an Immunoisolating Membrane System for Islet Xenotransplantation in Minipigs

Tova Neufeld,Shiri Maimon,Yoav Evron,Gordon C Weir,Ran Taube,Pnina Vardi,Stefan R Bornstein,Uriel Barkai,Eli C Lewis,Dmitri Azarov,Udi Willenz,Noa Shabtay,Tania Rozenshtein,Dana Lorber,Karina Yavriyants,Clark K Colton,Avi Rotem,Barbara Ludwig,Paul De Vos,Maria Balyura,Baruch Zimermann,Konstantin Bloch ,Anȷa Steffen

doi:10.1371/journal.pone.0070150

Abstract

Developing a device that protects xenogeneic islets to allow treatment and potentially cure of diabetes in large mammals has been a major challenge in the past decade. Using xenogeneic islets for transplantation is required in light of donor shortage and the large number of diabetic patients that qualify for islet transplantation. Until now, however, host immunoreactivity against the xenogeneic graft has been a major drawback for the use of porcine islets. Our study demonstrates the applicability of a novel immunoprotective membrane that allows successful xenotransplantation of rat islets in diabetic minipigs without immunosuppressive therapy. Rat pancreatic islets were encapsulated in highly purified alginate and integrated into a plastic macrochamber covered by a poly-membrane for subcutaneous transplantation. Diabetic Sinclair pigs were transplanted and followed for up to 90 days. We demonstrated a persistent graft function and restoration of normoglycemia without the need for immunosuppressive therapy. This concept could potentially offer an attractive strategy for a more widespread islet replacement therapy that would restore endogenous insulin secretion in diabetic patients without the need for immunosuppressive drugs and may even open up an avenue for safe utilization of xenogeneic islet donors.

Highlights

Islet transplantation for patients with type 1 diabetes is still an infrequently applied therapeutic approach performed only in highly specialized medical centers
The average weight of the recipients was stabilized at 9.561.25 kg (Table 1), about 3% above the minimal weight level
The major impediments to a successful and more widespread application of islet transplantation are the persistent shortage of donor organs, and the chronic need for immunsuppressive therapy to control allo- and autoimmunity [17,18]

Summary

Introduction

Islet transplantation for patients with type 1 diabetes is still an infrequently applied therapeutic approach performed only in highly specialized medical centers. The chronic need for immunosuppressive therapy following islet transplantation and the persistent shortage of highquality donor organs is currently restricting this therapeutic approach to a group of high-risk patients who have exhausted conservative treatment options. Only patients with unstable metabolic control, repeated severe hypoglycemia that is often associated with hypoglycemic unawareness, or those with rapidly progressive diabetes-associated complications are eligible for islet transplantation in most centers [4]. A thorough risk-benefit analysis is required to justify immunosuppressive therapy in patients suffering from a generally non-acute life-threatening disease [5]

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