New Avenue in Islet Transplantation by Macroencapsulation and Islet Pre-Treatment with Growth Hormone Releasing Hormone Agonist

Abstract

Introduction: Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications by reconstitution of endogenous insulin secretion. However, gradual loss in graft function over time due to insufficient oxygenation and inflammatory reactions, and chronic need for immunosuppression limit the outcome and the indication for islet transplantation. Methods: Here we present the approach of utilization of a macrochamber specially engineered for islet transplantation. The subcutaneous implantable device allows for controlled and adequate oxygen supply and provides immunological protection. In an isogeneic (n=16) and allogeneic (n=7) rodent model, pancreatic islets were embedded in alginate, integrated into the chamber-system and transplanted into Streptozotocin-induced diabetic rats. In addition, islets were pre-treated with growth hormone-releasing hormone (GHRH) agonist, JI-36. Prior to transplantation, islets were characterized for morphology and function by glucose stimulated insulin release, determination of oxygen consumption rate and immunohistochemistry. During the follow-up period of up to 90 days, blood glucose levels were measured daily and animals were subjected to an intravenous glucose tolerance test. The islet graft was removed at the end of the observation period to ensure recurrence of diabetes and enabling post-explantation assessment of the islet graft and the chamber surrounding tissue. Results: The subcutaneous chamber containing the islet graft normalized blood glucose in diabetic rodents for up to 3 months.Figure: [Metablic follow up of transplanted rodents]Sufficient graft function depended on oxygen supply. Pre-treatment with GHRH agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing in β-cell insulin reserve thereby allowing for a significant reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Despite complete avoidance of immunosuppression in the allogeneic transplantation model, no signs of rejection were observed, indicating a sufficient immunoisolation of the islet graft by the chamber system. Conclusion: A more efficient use of donor islets could facilitate the widespread use of islet transplantation as a treatment approach for type 1 diabetes. We investigated the combination of GHRH agonism with ideal oxygenation using a bioartificial macrochamber. Encapsulated islets are maintained within a device, which creates a sufficient immune barrier and allows for adequate oxygen supply to the islet graft. Together, a new strategy capable of restoring and maintaining long-term euglycemia in diabetic models is thereby presented. Consequently, this system opens up a novel strategy for β-cell replacement therapy without the need for immunosuppression and may even provide a promising avenue for future approaches to xenotransplantation.