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Control of IBMIR induced by fresh and cryopreserved hepatocytes by low molecular weight dextran sulfate
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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2017 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 1, 71-81 p.Article in journal (Refereed) Published
Abstract [en]

Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 mu g/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 mu g/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation.

Place, publisher, year, edition, pages
2017. Vol. 26, no 1, 71-81 p.
Keyword [en]
Innate immunity, IBMIR, Thromboinflammation, Hepatocyte transplantation, Low molecular weight dextran sulfate (LMW-DS)
National Category
Other Medical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-286868DOI: 10.3727/096368916X692609ISI: 000392785000007OAI: oai:DiVA.org:uu-286868DiVA: diva2:922110
Note

The manusripct of this article is part of the thesis Thromboinflammation: in a Model of Hepatocyte Transplantation http://uu.diva-portal.org/smash/record.jsf?pid=diva2:922111

Available from: 2016-04-22 Created: 2016-04-22 Last updated: 2017-11-30Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 123
National Category
Cell and Molecular Biology
Identifiers
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)
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Supervisors
Available from: 2016-05-20 Created: 2016-04-22 Last updated: 2016-06-15Bibliographically approved

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Gustafson, ElisabetAsif, SanaKozarcanin, HudaMeurling, StaffanEkdahl, Kristina Nilsson

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