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Islet Surface Heparinization Prevents the Instant Blood-Mediated Inflammatory Reaction in Islet Transplantation

¹ Division of Clinical Immunology, Department of Oncology, Radiology, and Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
² Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
³ Department of Transplantation Surgery, Rikshospitalet, Oslo, Norway
⁴ Department of Transplantation, University Hospital, Gothenburg, Sweden
⁵ Department of Nephrology and Transplantation, University Hospital, Malmö, Sweden
⁶ Division of Transplantation, Surgical Hospital, Helsinki University, Helsinki, Finland
⁷ Division of Transplantation Surgery, Department of Surgical Sciences, University Hospital, Uppsala, Sweden
⁸ Corline System, Uppsala, Sweden
⁹ Rudbeck Laboratory, Uppsala, Sweden

Address correspondence and reprint requests to Bo Nillson, The Rudbeck Laboratory C5, Dag Hammarskölds väg 20, SE-751 85 Uppsala, Sweden. E-mail: bo.nilsson{at}klinimm.uu.se

Abbreviations: APC, activated protein C; IBMIR, instant blood-mediated inflammatory reaction; MCP, monocyte chemoattractant protein; TAT, thrombin antithrombin

OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.

RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.

RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.

CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.

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