Absence of amyloid deposition in human islets transplantation after 13 years insulin independence.

Abstract

Although outcomes of clinical islet transplantation have constantly been improving over the past decades,1 achievement of sustained insulin independence still remains challenging for several reasons. After transplantation, islets are exposed to inflammatory responses, immune rejection, recurrence of autoimmunity, drug toxicity, and beta cell exhaustion. Widespread amyloid deposition was also described around transplanted islets that had lost their function.2 We have recently reported the longest insulin independence after islet transplantation.3,4 A kidney transplant recipient was infused with 8800 islets equivalent per kilogram body weight at the age of 36 years for poor metabolic control and repeated hypoglycemic episodes, and died of cerebral hemorrhage 13 years later with a fully functional graft. Because pretransplantation circulating C peptide was measurable (albeit close to the threshold of detection) and low levels of insulin were required, β-cell recovery in the native pancreas was suspected to participate in insulin independence.4 In this regard, autopsy revealed that the entire liver contained insulin-positive islets (Figure 1A). Islets were also present in the pancreas, but were negative for insulin; exceptionally, isolated β cells could be seen in the pancreatic parenchyma (Figure 1B–C). Glucagon positive cells were present in both organs, and rare somatostatin cells were observed in islets implanted in the liver. These data demonstrate that insulin independence was mediated by the islet graft and not through the regeneration of the native islets favored by chronic immunosuppression.Figure 1: 1. Histology of islets of Langerhans. A, Immunofluorescence staining of the liver, for insulin (blue), glucagon (red), and somatostatin (green). Transplanted islets are seen and made up mainly of β cells. Glucagon-positive cells border the core of the islets, whereas somatostatin-positive cells are only rarely found. B and C, Immunofluorescence staining of the native pancreas, for insulin (blue), glucagon (green), and somatostatin (red). Islets in the pancreas do not stain for insulin. Only rare, single β cells are seen in the pancreas, outside islet structures (white arrows), whereas glucagon and somatostatin positive cells are abundantly present within the islets. D, Same specimen as panel A stained with H&E and Congo red. Rare extracellular deposits of amyloid are found in contact with the transplanted islets (black arrow). Scale bars, 100 μm. Amyloid deposition was analyzed on 12 separate liver sections originating from the left and right liver (peripheral and central part). Each slide contains between 8 and 16 islets structures. Congo red–positive control was based on human kidney with amyloidosis (kindly provided by the Department of Pathology, Geneva University Hospitals, and University of Geneva).Pancreatic islet amyloid is mainly composed of the polypeptide hormone or the islet amyloid polypeptide, which is released upon stimulation of the β cells.5 Excessive insulin secretion leads to extracellular amyloid deposition, which induces progressive beta cells dysfunction and death via cytotoxic mechanisms. This phenomenon has been well described in patients with type 2 diabetes and has also been suggested to contribute to failure of islet transplantation.2 Therefore, we have explored the presence of amyloid deposition around the transplanted islets. Congo red staining revealed near-absent amyloid deposits around the islets in the liver (Figure 1D). The absence of amyloid deposition may have been favored in this case by the low insulin secretion by transplanted beta cells, as suggested by low insulin requirements of the patient (16 IU/day) before transplantation. Overall, this case report demonstrates that allogeneic islets of Langerhans can survive several years within the liver. As expected from the literature data, amyloid deposition was only rarely observed in this patient. Further studies are warranted to confirm the relation between basal insulin requirement and amyloid deposition in human islet transplantation.