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Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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2002 (English)In: Lancet, ISSN 12504401, Vol. 360, no 9350, 2039-45 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 360, no 9350, 2039-45 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-95687OAI: oai:DiVA.org:uu-95687DiVA: diva2:169997
Available from: 2007-04-04 Created: 2007-04-04 Last updated: 2015-06-15Bibliographically approved
In thesis
1. Mechanisms and Therapeutic Interventions of Instant Blood-Mediated Inflammatory Reaction (IBMIR)
Open this publication in new window or tab >>Mechanisms and Therapeutic Interventions of Instant Blood-Mediated Inflammatory Reaction (IBMIR)
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Intraportal transplantation of isolated islets of Langerhans is a procedure approaching clinical acceptance as a treatment for patients with type I diabetes mellitus. One major problem with this treatment is that large amounts of cells are lost at the time of infusion into the portal vein, resulting in a low level of engraftment of the islets. One likely explanation for this loss is the instant blood-mediated inflammatory reaction (IBMIR), a thrombotic/inflammatory reaction occurring when islets come in contact with blood. The IBMIR is characterized by coagulation and complement activation, leading to platelet consumption, leukocyte infiltration of the islets, and disruption of islet integrity.

In this thesis, the IBMIR is shown to be triggered by tissue factor (TF), the main initiator of blood coagulation in vivo. TF is expressed in two forms by the endocrine cells of the pancreas, a full-length membrane-bound and an alternatively spliced soluble form. Blocking TF in vitro efficiently reduces the macroscopic clotting, expression of coagulation activation markers, and leukocyte infiltration. This blockade can be achieved by adding either an active site-specific anti-TF antibody or site-inactivated FVIIa that competes with active FVIIa in the blood. TF may be secreted from the islets, since it is colocalized with insulin and glucagon in their granules. The IBMIR has also been demonstrated in vivo in patients transplanted with isolated islets.

There are two ways to block the IBMIR in transplantation: systemic treatment of the patients, or islet pretreatment before transplantation to reduce their thrombogenicity. In this thesis, low molecular weight dextran sulfate (LMW-DS) is shown to reduce activation of the complement and coagulation systems and decrease the cell infiltration into the islets in vitro and in vivo, in both a xenogenic and an allogenic setting. Based on these results, LMW-DS is now in clinical trials.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 48 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 249
Immunology, Diabetes, Islet transplantation, Islets of Langerhans, Coagulation activation, Complement activation, IBMIR, Tissue factor, Low molecular weight dextran sulfate, Immunologi
urn:nbn:se:uu:diva-7786 (URN)978-91-554-6851-4 (ISBN)
Public defence
2007-04-28, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarsköldsväg 20, Uppsala, 09:00
Available from: 2007-04-04 Created: 2007-04-04Bibliographically approved

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