Islet Transplantation in Type 1 Diabetes Mellitus Using Cultured Islets and Steroid‐Free Immunosuppression: Miami Experience

Abstract

Following the success obtained with transplantation of fresh human islets under steroid-free immunosuppression, this trial evaluated the transplantation of islets that had undergone a period of in vitro culture and the potential of tumor necrosis factor (TNF-a) blockade to improve islet engraftment. Subjects included 16 patients with type 1 diabetes mellitus (T1DM); half were randomly assigned to receive Infliximab immediately preceding initial infusion. Immunosuppression consisted of daclizumab induction and sirolimus/tacrolimus maintenance. Out of 16 subjects 14 achieved insulin independence with one or two islet infusions; adverse events precluded completion in two. Without supplemental infusions, 11/14 (79%) subjects were insulin independent at 1 year, 6/14 (43%) at 18 months; these same subjects remain insulin independent at 33 ± 6 months. While on immunosuppression, all patients maintained graft function. Out of 14 patients, 8 suffered chronic partial graft loss, likely immunological in nature, 5 of these received supplemental infusions. Currently, 11 subjects remain on immunosuppression, 8 (73%) are insulin independent, two with supplemental infusions. Insulin independent subjects demonstrated normalization of HbA1c, fructosamine and Mean Amplitude of Glycemic Excursions (MAGE) values. No clinical benefit of infliximab was identified. These results demonstrate that transplantation of cultured human islet allografts results in reproducible insulin independence in all subjects under this immunosuppressive regimen, comparable to that of freshly transplanted islets (Edmonton protocol).

Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet‐transplantation enhances immediate post‐transplant islet graft function but not long‐term normoglycemia

“…These complications can be prevented by transplanting an endogenous insulin source such as pancreatic islets that regulate glucose levels from a minute‐to‐minute level 2. Currently islets are infused into the liver as clinical standard, but widespread application of this therapy is limited due to the lack of long‐term success: within 5 years after clinical islet transplantation <50% of the patients remain normoglycemic 3, 4. The liver as transplantation side is considered to be a major contributor to these low success rates.…”

Sustained insulin secretory response in human islets co-cultured with pancreatic duct-derived epithelial cells within a rotational cell culture system

“…The optimal isolation and pre-culture of human islets have been shown to be pertinent to successful clinical islet transplantation [1,2], yet both procedures also have detrimental effects. Disruption of the complex cytoarchitecture of the human islet as a consequence of isolation leads to a loss of both structural and functional integrity [3][4][5], and pretransplant culture is associated with a decline in beta cell mass [6,7] concomitant with a marked diminution in glucose sensitivity [8,9].…”

Autocrine insulin action activates Akt and increases survival of isolated human islets

“…Although the original Edmonton protocol involved transplanting islets immediately following isolation, the recovery of islets in culture prior to transplantation has once again become common practice [1,18]. One reason for culturing islets prior to transplantation is that a significant amount of islet cell death due to the isolation occurs during the 48 h following isolation, and thus it is advantageous to allow these cells to die off in culture so as not to provoke additional local inflammation at the graft site.…”