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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, Clinical Immunology.
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2002 (English)In: Lancet, Vol. 360, no December 21/28, 2039-2045 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 360, no December 21/28, 2039-2045 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91759OAI: oai:DiVA.org:uu-91759DiVA: diva2:164594
Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2015-06-15Bibliographically approved
In thesis
1. The Role of Innate Immunity in Islet Transplantation: Clinical and Experimental Studies
Open this publication in new window or tab >>The Role of Innate Immunity in Islet Transplantation: Clinical and Experimental Studies
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Clinical islet transplantation is an emerging procedure to cure type 1 diabetes. The graft is implanted by infusion into the liver through the portal vein. A major obstacle that still needs to be overcome is the requirement for islets from multiple donors to achieve insulin independence.

An innate inflammatory reaction, the IBMIR, is elicited when islets are exposed to blood. The IBMIR has been described as a clotting reaction culminating in disruption of islet morphology and is a plausible cause for loss of tissue during the early post-transplant period.

In this thesis, the underlying mechanisms of the IBMIR were characterized. The IBMIR was for the first time demonstrated in patients undergoing an islet transplant, and a number of clinically applicable strategies to limit this reaction were identified.

The thrombin inhibitor melagatran completely blocked the IBMIR in an in vitro tubing blood loop system, indicating that thrombin is the driving force in the reaction. Interestingly, islets were shown to produce and secrete tissue factor (TF), the physiological trigger of coagulation. Inactivated FVIIa, a specific inhibitor of TF, successfully blocked initiation of the IBMIR. An alternative approach to limit the IBMIR was to pre-treat islets in culture prior to transplantation. Nicotinamide added to the culture medium effectively decreased the level of TF in human islets. Infiltration of immune cells, also a part of the IBMIR, was characterized in detail. The predominant cell types infiltrating the islets were neutrophilic granulocytes and, to a lesser degree, monocytes. Both cell types may exert direct cytotoxic effects, and the antigen-presenting monocytes may also be important for directing the specific immune system to the site of inflammation.

These findings have provided new insight into the nature of the IBMIR and offer several new strategies to improve the outcome of clinical islet transplantation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 75 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1352
Immunology, diabetes, islet transplantation, islet of Langerhans, coagulation activation, IBMIR, tissue factor, thrombin, inactivated FVIIa, melagatran, neutrophilic granulocyte, Immunologi
National Category
Immunology in the medical area
urn:nbn:se:uu:diva-4260 (URN)91-554-5966-8 (ISBN)
Public defence
2004-05-19, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Available from: 2004-04-26 Created: 2004-04-26Bibliographically approved

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