Editors' ChoiceDiabetes

Transplanting islets: Hitting two birds with one stone

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Science Translational Medicine  29 Aug 2018:
Vol. 10, Issue 456, eaav1611
DOI: 10.1126/scitranslmed.aav1611

Abstract

A chemically modified alginate-based encapsulation strategy combined with transplantation into the bursa omentalis maintains islet graft function in nonhuman primates.

Patients with type 1 diabetes mellitus (T1DM) require lifelong insulin injections. Some at-risk T1DM patients have poor blood glucose control (known as brittle diabetes) or are unaware that their blood glucose falls to critically low levels during insulin therapy, thereby fulfilling the criteria for islet transplantation therapy. Despite relieving from insulin therapy in the short term, long-term effectiveness of islet transplantation is limited by gradual loss of islet graft function. In this study, Bochenek et al. show that an alginate formulation for islet encapsulation combined with a novel transplantation strategy optimized long-term survival of islets in nonhuman primates.

The authors first evaluated the effects of seven alginate formulations for islet encapsulation, including three formulations previously tested in clinical trials and three chemically modified and immune-modulating alginate formulations. Each of the seven formulations was implanted as empty spheres into the intraperitoneal cavity of nonhuman primates (NHPs). Although the clinically tested alginate formulations triggered foreign body immune responses and subsequent fibrotic overgrowth, which contributed to the loss of graft function reported in the clinical trials, these responses were reduced in chemically modified alginate formulations.

Other factors that contribute to gradual islet failure are the tendency for transplanted islets to clump together and the hypoxic environment within the intraperitoneal space. To address this, the researchers investigated alternative transplantation sites with environments that might better accommodate encapsulated islet grafts. Minimally invasive implantation of alginate spheres encapsulating allogeneic islets into the bursa omentalis (the sac behind the intraperitoneal space) of NHPs provided better spatial islet distribution. This site was marginally less hypoxic compared with the intraperitoneal space.

Last, the researchers selected the most effective chemically modified alginate formulation, Z1-Y15, for allogeneic islet encapsulation and transplantation into the bursa omentalis of nondiabetic NHPs. Insulin secretion and intracellular signaling of the retrieved islets were maintained, with no significant loss of viability four months posttransplantation.

Future studies would need to validate the islet encapsulation and transplantation technique in primate models of T1DM, with parameters such as blood glucose and insulin levels evaluated in vivo before testing in the clinic. If this combination strategy holds similar promise in diabetic models in vivo, it has the potential to greatly improve the status of islet transplantation for T1DM treatment.

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