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Diabetes 54:1755-1762, 2005
© 2005 by the American Diabetes Association, Inc.

Tissue Factor Produced by the Endocrine Cells of the Islets of Langerhans Is Associated With a Negative Outcome of Clinical Islet Transplantation

Helena Johansson1, Agneta Lukinius2, Lisa Moberg1, Torbjörn Lundgren3, Christian Berne4, Aksel Foss5, Marie Felldin6, Ragnar Källen7, Kaija Salmela8, Annika Tibell3, Gunnar Tufveson9, Kristina Nilsson Ekdahl1,10, Graciela Elgue1, Olle Korsgren1, and Bo Nilsson1

1 Department of Radiology, Oncology and Clinical Immunology, Division of Clinical Immunology, The Rudbeck Laboratory, University Hospital, Uppsala, Sweden
2 Department of Genetics and Pathology, Division of Pathology, The Rudbeck Laboratory, University Hospital, Uppsala, Sweden
3 Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
4 Department of Medical Sciences, Division of Medicine, University Hospital, Uppsala, Sweden
5 Department of Transplantation Surgery, Rikshospitalet, Oslo, Norway
6 Department of Transplantation, University Hospital, Gothenburg, Sweden
7 Department of Nephrology and Transplantation, University Hospital, Malmö, Sweden
8 Division of Transplantation, Surgical Hospital, Helsinki University, Helsinki, Finland
9 Department of Surgical Sciences, Division of Transplantation Surgery, University Hospital, Uppsala, Sweden
10 Department of Chemistry and Biomedical Sciences, University of Kalmar, Kalmar, Sweden

There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low–molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15–60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets.

Address correspondencereprint requests to Helena Johansson, The Rudbeck Laboratory, University Hospital, 751 85 Uppsala, Sweden. E-mail: helena.johansson{at}klinimm.uu.se

Abbreviations: FVIIa, factor VIIa, FVIIa-AT, FVIIa-antithrombin complex; IBMIR, instant blood-mediated inflammatory reaction; mAbs, monoclonal antibodies; TAT, thrombin-antithrombin complex


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