Inhibition of Thrombin Abrogates the Instant Blood-Mediated Inflammatory Reaction Triggered by Isolated Human Islets
Possible Application of the Thrombin Inhibitor Melagatran in Clinical Islet Transplantation
- Lisa Özmen1,
- Kristina Nilsson Ekdahl12,
- Graciela Elgue1,
- Rolf Larsson1,
- Olle Korsgren1 and
- Bo Nilsson1
- 1Department of Radiology, Oncology and Clinical Immunology, Division of Clinical Immunology, the Rudbeck Laboratory, University Hospital, Uppsala, Sweden
- 2Department of Chemistry and Biomedical Science, University of Kalmar, Kalmar, Sweden
Abstract
A thrombotic/inflammatory reaction is elicited when isolated islets of Langerhans come in contact with ABO-compatible blood. The detrimental effects of this instant blood-mediated inflammatory reaction (IBMIR) provide a reasonable explanation for the observation that an unexpectedly high number of islets, from several donors, are needed to produce normoglycemia in transplant patients with type 1 diabetes. In this study, the hypothesis that a specific thrombin inhibitor, Melagatran, could reduce IBMIR in an in vitro model in which human islets are exposed to ABO-compatible blood was tested. The administration of Melagatran abrogated IBMIR dose-dependently. Islets exposed to blood, in the absence or presence of 0.4 μmol/l Melagatran, exhibited a loss of integrity and were found to be trapped in macroscopic clots containing platelets and CD11b+ leukocytes. At concentrations from 1 to 10 μmol/l, Melagatran inhibited both coagulation and complement activation. Also, platelet and leukocyte activation and consumption were decreased. Islet morphology was maintained with almost no platelets adhering to the surface, and infiltration by CD11b+ leukocytes was considerably reduced. In conclusion, Melagatran significantly reduced IBMIR in this model system. This protective effect indicates that thrombin plays a pivotal role in IBMIR and suggests that thrombin inhibition can improve the outcome of clinical islet transplantation.
Footnotes
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Address correspondence and reprint requests to Bo Nilsson, MD, Department of Radiology, Oncology and Clinical Immunology, Division of Clinical Immunology, the Rudbeck Laboratory, University Hospital, S-75185 Uppsala, Sweden. E-mail: bo.nilsson{at}klinimm.uu.se.
Received for publication 5 November 2001 and accepted in revised form 25 February 2002.
β-TG, β-thromboglobulin; FXIa-AT, factor XIa-antithrombin complex; EIA, enzyme immunoassay; HRP, horseradish peroxidase; IBMIR, instant blood-mediated inflammatory reaction; PMN, polymorphonuclear cells; TAT, thrombin-antithrombin complex.
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