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The Instant Blood-Mediated Inflammatory Reaction Characterized in Hepatocyte Transplantation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
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2011 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 91, no 6, 632-638 p.Article in journal (Refereed) Published
Abstract [en]

Background. Hepatocyte transplantation (HcTx) has proven to be a safe procedure, although the functional results have been unsatisfactory, probably due to insufficient engraftment or a loss of transplanted mass or function. In this study, we investigate whether hepatocytes in contact with blood induce an inflammatory reaction leading to, similar to what happens in clinical islet transplantation, an instant blood-mediated inflammatory reaction (IBMIR) resulting in an early loss of transplanted cells. Methods. By using an experimental model that mimics the portal vein blood flow, we could study different parameters reflecting the effects on the innate immunity elicited by hepatocytes in contact with ABO-matched human blood. Results. We report that all aspects of the IBMIR such as platelet and granulocyte consumption, coagulation, and complement activation were demonstrated. Addition of various specific inhibitors of coagulation allowed us to clearly delineate the various stages of the hepatocyte-triggered IBMIR and show that the reaction was triggered by tissue factor. Analysis of a case of clinical HcTx showed that hepatocyte-induced IBMIR also occurs in vivo. Both the inflammatory and the coagulation aspects were controlled by low-molecular-weight dextran sulfate. Conclusion. Isolated hepatocytes in contact with blood induce the IBMIR in vitro, and there are indications that these events are also relevant in vivo. According to these findings, HcTx would benefit from controlling a wider range of signals from the innate immune system.

Place, publisher, year, edition, pages
2011. Vol. 91, no 6, 632-638 p.
Keyword [en]
IBMIR, Islet transplantation, Cell transplantation, Innate immunity, Engraftment
National Category
URN: urn:nbn:se:uu:diva-149561DOI: 10.1097/TP.0b013e31820ae459ISI: 000288115800016PubMedID: 21289595OAI: oai:DiVA.org:uu-149561DiVA: diva2:405278
Available from: 2011-03-22 Created: 2011-03-21 Last updated: 2016-07-19Bibliographically approved
In thesis
1. Thromboinflammation: in a Model of Hepatocyte Transplantation
Open this publication in new window or tab >>Thromboinflammation: in a Model of Hepatocyte Transplantation
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hepatocyte transplantation is an attractive method for the treatment of metabolic liver disease and acute liver failure. The clinical application of this method has been hampered by a large initial loss of transplanted cells.

This thesis has identified and characterized an instant blood-mediated inflammatory reaction (IBMIR), which is a thromboinflammatory response from the innate immunity that may partly explain the observed loss of cells. In vitro perifusion experiments were performed and established that hepatocytes in contact with blood activate the complement and coagulation systems and induce clot formation in conjunction with the recruitment of neutrophils.  Within an hour, the hepatocytes were surrounded by platelets and entrapped in a clot infiltrated by neutrophils. Furthermore, hepatocytes expressed tissue factor (TF), and the reactions were shown to be initiated through the TF pathway. Monitoring of hepatocyte transplantation in vivo revealed activation of the same parameters as were noted in vitro.

For the first time, von Willebrand factor (vWF) was identified on the hepatocyte surface, being demonstrated by flow cytometry and confocal microscopy. mRNA for vWF was also confirmed in hepatocytes. Complex formation between platelets and hepatocytes was also identified. Addition of antibodies targeting the binding site for vWF on the platelets reduced the complex formation.

Two different strategies, systemic and local intervention, were applied to diminish the thromboinflammation elicited from the hepatocytes in contact with ABO-matched blood. Systemic inhibition with LMW-DS, in a clinically applicable dose, was found to be superior in controlling the IBMIR in vitro when compared to heparin. Cryopreserved hepatocytes elicited the IBMIR to the same extent as did fresh hepatocytes, and the IBMIR was equally well controlled with LMW-DS in both cryopreserved and fresh cells.

Hepatocytes were coated with two layers of immobilized heparin in an attempt to protect the cells from the IBMIR. In vitro perifusion experiments showed heparinized hepatocytes triggered a significantly lower degree of IBMIR.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 75 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 123
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-286869 (URN)978-91-554-9592-3 (ISBN)
Public defence
2016-06-10, Rosénsalen, Akademiska Barnsjukhuset Ing 95/96, Uppsala, 10:00 (Swedish)
Available from: 2016-05-20 Created: 2016-04-22 Last updated: 2016-06-15Bibliographically approved

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Gustafson, Elisabet K.Haglund, UlfKorsgren, OlleNilsson, Bo
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