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Islet Surface Heparinization Prevents the Instant-Blood Mediated Inflammatory Reaction in Islet Transplantation
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. (Ö-cellslab)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. (Komplement och Biomaterial)
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2007 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, nr 8, s. 2008-2015Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2007. Vol. 56, nr 8, s. 2008-2015
Nyckelord [en]
APC, activated protein C, IBMIR, instant blood-mediated inflammatory reaction, MCP, monocyte chemoattractant protein, TAT, thrombin antithrombin
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-96505DOI: 10.2337/db07-0358ISI: 000248473100007PubMedID: 17540953OAI: oai:DiVA.org:uu-96505DiVA, id: diva2:171102
Tillgänglig från: 2007-11-15 Skapad: 2007-11-15 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. Pancreatic Islet Transplantation: Modifications of Islet Properties to Improve Graft Survival
Öppna denna publikation i ny flik eller fönster >>Pancreatic Islet Transplantation: Modifications of Islet Properties to Improve Graft Survival
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

During the past decade clinical islet transplantation has become a viable strategy for curing type 1 diabetes. The limited supply of organs, together with the requirement for islets from multiple donors to achieve insulin independence, has greatly limited the application of this approach.

The islets are infused into the liver via the portal vein, and once exposed to the blood, the grafted tissue has been shown to be damaged by the instant blood-mediated inflammatory reaction (IBMIR), which is characterized by coagulation and complement activation as well as leukocyte infiltration into the islets. Islet revascularization is a subsequent critical step for the long-term function of the transplanted graft, which may partially be impeded by the IBMIR.

In this thesis, we have explored novel strategies for circumventing the effects of the IBMIR and facilitating islet revascularization.

Systemic inhibitors of the IBMIR are typically associated with an increased risk of bleeding. We therefore evaluated alternative strategies for modulating the islets prior to transplantation. We demonstrated, using an adenoviral vector, that a high level of expression and secretion of the anticoagulant hirudin could be induced in human islets. An alternative approach to limiting the IBMIR was developed in which anticoagulant macromolecular heparin complexes were conjugated to the islet surface. This technique proved effective in limiting the IBMIR in both an in vitro blood loop model and an allogeneic porcine model of islet transplantation. An increased adhesion of endothelial cells to the heparin-coated islet surface was demonstrated, as was the capacity of the heparin conjugate to bind the angiogenic factors VEGF and FGF; these results have important implications for the revascularization process.

The outcome of the work in this thesis suggests that modulation of the islet surface is an attractive alternative to systemic therapy as a strategy for preventing the IBMIR. Moreover, the same techniques can be employed to induce revascularization and improve the engraftment of the transplanted islets. Ultimately, improved islet viability and engraftment will make islet transplantation a more effective procedure and increase the number of patients whose diabetes can be cured.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2007. s. 60
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 297
Nyckelord
Medicine, Diabetes, islet transplantation, islets of Langerhans, coagulation activation, IBMIR, hirudin, heparin, growth factor, angiogenesis, Medicin
Identifikatorer
urn:nbn:se:uu:diva-8333 (URN)978-91-554-7039-5 (ISBN)
Disputation
2007-12-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Opponent
Handledare
Tillgänglig från: 2007-11-15 Skapad: 2007-11-15 Senast uppdaterad: 2011-01-12Bibliografiskt granskad

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