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Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation
Abstract
Background Intraportal transplantation of pancreatic islets offers improved glycaemic control and insulin independence in type 1 diabetes mellitus, but intraportal thrombosis remains a possible complication. The thrombotic reaction may explain why graft loss occurs and islets from more than one donor are needed, since contact between human islets and ABO-compatible blood in vitro triggers a thrombotic reaction that damages the islets. We investigated the possible mechanism and treatment of such thrombotic reactions. Methods Coagulation activation and islet damage were monitored in four patients undergoing clinical islet transplantation according to a modified Edmonton protocol. Expression of tissue factor (TF) in the islet preparations was investigated by immunohistochemistry, immunoprecipitation, electron microscopy, and RT-PCR. To assess TF activity in purified islets, human islets were mixed with non-anticoagulated ABO-compatible blood in tubing loops coated with heparin. Findings Coagulation activation and subsequent release of insulin were found consistently after clinical islet transplantation, even in the absence of signs of intraportal thrombosis. The endocrine, but not the exocrine, cells of the pancreas were found to synthesise and secrete active TF. The clotting reaction triggered by pancreatic islets in vitro could be abrogated by blocking the active site of TF with specific antibodies or site-inactivated factor VIIa, a candidate drug for inhibition of TF activity…
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“One consequence of this direct blood contact is an immune response called the instant blood-mediated inflammatory reaction (IBMIR).”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
In the citing paper
“It is thought that a major cause of the initial islet death observed in the immediate aftermath of portal vein islet infusion is due to IBMIR.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
In the citing paper
“Within 15 minutes of contact with host blood, islets are encapsulated within a layer of platelets, reducing nutrient diffusion.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
In the citing paper
“Furthermore, leukocytes infiltrate the islets within an hour, leading to cell death.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [139]
In the citing paper
“Because conventional islet transplantation by infusion into the hepatic portal vein suffers from certain limitations, such as acute graft loss triggered by an instant blood-mediated inflammatory response (IBMIR)”
From Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. (2024) · cites this paper as [24]
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“Islets and beta cells express TF under normal conditions [7, 8] and islet TF has been studied in the field of islet transplantation, wherein TF coagulant activity promotes clot formation, leading to islet cell death after transplantation [8, 9].”
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“This instant blood-mediated inflammatory reaction (IBMIR) occurs secondary to the brisk activation of coagulation and complement cascades, which are triggered by exposure to human blood [10].”
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“have demonstrated that islets contribute to the initiation of IBMIR by expressing tissue factor.(9,10,12) However, little research has been done to analyze the molecular events within islets that take place following exposure type 1 diabetic blood, which in turn could shed light on key molecules and signaling pathways…”
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“Under such pro-inflammatory conditions, the expression of tissue factor (TF), the cellular initiator of coagulation, is induced in leukocytes, endothelial and also insulinsecreting cells that all shed MP bearing the active form of TF thereby promoting coagulation close to the islets [10, 12, 13].”
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“We and others have demonstrated that tissue factor (TF) and monocyte chemoattractant protein-1 (MCP-1) expressed on the grafted islets elicit the IBMIR [4–9].”
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“induces an innate immune response called ‘immediate-blood mediated inflammatory reaction’ (IBMIR) in which islet-derived chemokines and tissue factor cause activation of the coagulation and complement systems and result in platelet binding to the islet surface and perigraft fibrin/clot deposition [32,33].”
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“On the basis of these findings, we hypothesize that ATIII may have a beneficial effect on inhibiting inflammatory responses in the liver of mice receiving islets soon after transplantation leading to protection of transplanted islets from innate immune rejection because there is an evidence that coagulation is involve…”
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“However, other immune challenges remain significant, particularly the instant blood-mediated inflammatory reaction (IBMIR), which triggers a robust xeno-immune response [83,84].”
Einstein, S. A., Steyn, L. V., Weegman, B. P., Suszynski, T. M., Sambanis, A., O’Brien, T. D., Avgoustiniatos, E. S., Firpo, M. T., Graham, M. L., Janecek, J. L., et al. (2023) · Frontiers in Transplantation · doi:10.3389/frtra.2023.1257029 · Cited by 12
Preferable Transplant Site for Hepatocyte Transplantation in a Rat Model
Ogasawara, H., Inagaki, A., Fathi, I., Imura, T., Yamana, H., Saitoh, Y., Matsumura, M., Fukuoka, K., Miyagi, S., Nakamura, Y., et al. (2021) · Cell Transplantation · doi:10.1177/09636897211040012 · Cited by 14
Parajuli, K., Zhang, Y.-Q., Cao, A., Wang, H.-J., Fonseca, V., & Wu, H. (2020) · Cell Transplantation · doi:10.1177/0963689720958655 · Cited by 10
Tokodai, K., Kumagai-Braesch, M., Karadagi, A., Johansson, H., Ågren, N., Jorns, C., Ericzon, B., & Ellis, E. C. S. (2020) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2019.07.001 · Cited by 10
Self-citationRegulation of c-Jun NH2-Terminal Kinase for Islet Transplantation
Noguchi, H. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8111763 · Cited by 10
Kosinová, L., Pátíková, A., Jirák, D., Gálisová, A., Vojtíšková, A., Saudek, F., & Kříž, J. (2019) · Islets · doi:10.1080/19382014.2019.1651164 · Cited by 10
“that islet grafts isolated from more than one donor are required to achieve insulin independence of a diabetic patient in clinical practice.(4,7-9) Several intervention strategies improving islet engraftment by inhibition of coagulation and/or inflammation have been reported,(8-14) however, a technique for quantificat…”
BackgroundMethodEspes, D., Lau, J., & Carlsson, P. (2017) · European Journal of Endocrinology · doi:10.1530/eje-17-0080 · Cited by 10
Ock, S., Lee, J., Oh, K. B., Hwang, S., Yun, I.-J., Ahn, C., Chee, H., Kim, H., Park, J., Kim, S. J., et al. (2016) · Xenotransplantation · doi:10.1111/xen.12249 · Cited by 10
“Previous studies have also shown that IGs derived from genetically modified pigs harboring double GalT-KO have certain advantages, such as reducing IBMIR-related graft loss and protecting islets from the primate immune response [6,10], consistent with our current findings.”
BackgroundEsposito, A., Palmisano, A., Maffi, P., Malosio, M. L., Nano, R., Canu, T., COBELLI, F. D., Piemonti, L., Ironi, G., Secchi, A., et al. (2013) · American Journal of Transplantation · doi:10.1111/ajt.12501 · Cited by 10
“Moreover, the microvascular damage induced during isolation and preparation leads islets to express the tissue factor that activates the pro-coagulant pathways determining the so-called instant blood-mediated inflammatory reaction (IBMIR) immediately after intraportal infusion (19,20).”
BackgroundCabric, S., Elgue, G., Nilsson, B., Korsgren, O., & Schmidt, P. (2006) · Cell Transplantation · doi:10.3727/000000006783464390 · Cited by 10
Self-citationInverardi, L., & Ricordi, C. (2006) · Transplantation · doi:10.1097/01.tp.0000228879.22020.0f · Cited by 10
“IBMIR occurs in the clinical setting, and it is likely to lead to early/immediate loss of a significant portion of the transplanted tissue in clinical trials of islet allotransplantation (6).”
BackgroundKunugi, S., & Yamaoka, T. (2012) · doi:10.1007/978-3-642-27856-3 · Cited by 10
“The basic idea of gene therapy involves delivery of an exogenous gene into the cells to express the encoded protein, which may be insufficiently or aberrantly expressed naturally [128].”
BackgroundSkog, O., & Korsgren, O. (2019) · Acta Diabetologica · doi:10.1007/s00592-019-01420-8 · Cited by 13
Self-citationRoles of Islet Toll-Like Receptors in Pig to Mouse Islet Xenotransplantation
Han, R., Lee, E. W., Hong, J. H., Han, K., Yeom, H., Kim, H., Kim, M.-G., Jung, H., Oh, K., Park, K., et al. (2013) · Cell Transplantation · doi:10.3727/096368912x657684 · Cited by 9
“Tissue factor induction on the islet surface triggers IBMIR (37), and induction of Fgl-2 contributes to thrombosis during acute vascular xenograft rejection (19).”
BackgroundInfluentialHybrid cellular spheroids from hepatocellular carcinoma and insulin-secreting cell lines.
Kim, J., Kim, H. W., Bae, S., Joo, D., Huh, K., Fang, Y.-H., Cho, Y., Jeong, J., Kim, Y., & Lee, J. (2012) · Transplantation Proceedings · doi:10.1016/j.transproceed.2012.02.016 · Cited by 9
Culture and Transportation of Human Islets Between Centers
Ichii, H., Pileggi, A., Khan, A., Fraker, C. A., & Ricordi, C. (2007) · CRC Press eBooks · doi:10.3109/9781420016512-15 · Cited by 9
Avoiding damage to transplanted human islets during implantation is important.
Gray, D. (2005) · Transplantation · doi:10.1097/01.tp.0000157274.88555.04 · Cited by 9
“The Uppsala group identified the initiating cause of the clotting cascade as the expression of tissue factor (TF) (3).”
BackgroundEvidence that tilapia islets do not express α‐(1,3)gal: implications for islet xenotransplantation
Leventhal, J., Sun, J., Zhang, J., Galili, U., Chong, A., Baker, M., Kaufman, D., & Wright, J. R. (2004) · doi:10.1111/j.1399-3089.2004.00133.x · Cited by 9
“Furthermore, the interaction of porcine islets with human blood has been linked to a deleterious prothrombotic, inflammatory response which leads to islet loss [13,31].”
BackgroundCooper, D., & Byrne, G. W. (2020) · doi:10.1007/978-3-030-49127-7 · Cited by 9
Saeki, Y., Ishiyama, K., Ishida, N., Tanaka, Y., & Ohdan, H. (2017) · Transplantation Proceedings · doi:10.1016/j.transproceed.2016.10.010 · Cited by 9
Hawthorne, W. J., Williams, L. J., & Chew, Y. V. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-39824-2_7 · Cited by 12
Design of Biointerfaces for Regenerative Medicine
Arima, Y., Kato, K., Teramura, Y., & Iwata, H. (2011) · doi:10.1007/12_2011_161 · Cited by 9
“These host defense mechanisms destroy donor islets because they are considered foreign bodies [129-131].”
BackgroundVivot, K., Benahmed, M. A., Seyfritz, E., Bietiger, W., Elbayed, K., Ruhland, E., Langlois, A., Maillard, É., Pinget, M., Jeandidier, N., et al. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.15189 · Cited by 7
“Indeed, rapidly after islet infusion, islets suffer from an inflammatory reaction, the instant blood-mediated inflammatory reaction (IBMIR) [6,7], combined with hypoxia as vascular connections of islets are broken”
BackgroundInfluentialShahbazov, R., Kanak, M., Takita, M., Kunnathodi, F., Khan, O. S., Borenstein, N., Lawrence, M. C., Levy, M., & Naziruddin, B. (2016) · Diabetes/Metabolism Research Reviews · doi:10.1002/dmrr.2714 · Cited by 8
Kloster‐Jensen, K., Sahraoui, A., Vethe, N. T., Korsgren, O., Bergan, S., Foss, A. E., & Scholz, H. (2016) · Journal of Diabetes Research · doi:10.1155/2016/4196460 · Cited by 8
Self-citationPotential benefits and risks of clinical xenotransplantation
Cooper, D., & Ayares, D. (2012) · doi:10.2147/trrm.s31481 · Cited by 8
Iino, S., Abeyama, K., Kawahara, K., Aikou, T., & Maruyama, I. (2004) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2004.00673.x · Cited by 8
Progress in Islet Transplantation in Patients with Type 1 Diabetes Mellitus
Truong, W., & Shapiro, A. M. J. (2006) · Treatments in Endocrinology · doi:10.2165/00024677-200605030-00003 · Cited by 8
Turan, A., Zhang, L., Tarique, M., Ulker, V., Arguc, F., Badal, D., Yolcu, E., & Shirwan, H. (2023) · American Journal of Transplantation · doi:10.1016/j.ajt.2023.02.021 · Cited by 7
Saudek, F., Hladiková, Z., Hagerf, B., Nemetova, L., Girman, P., Kříž, J., Marada, T., Habart, D., Berková, Z., Leontovyc, I., et al. (2022) · Transplantation Proceedings · doi:10.1016/j.transproceed.2021.11.037 · Cited by 7
Induction of Immune Tolerance in Islet Transplantation Using Apoptotic Donor Leukocytes
Sato, N., & Marubashi, S. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10225306 · Cited by 8
“Previous studies have shown that islet isolation induced proinflammatory cytokines and danger signals, including TNFa [59], monocyte chemoattractant protein-1 [60], and tissue factor [61].”
BackgroundThe therapeutic role of endothelial progenitor cells in Type 1 diabetes mellitus.
Grapensparr, L., Olerud, J., Vasylovska, S., & Carlsson, P. (2011) · Regenerative medicine · doi:10.2217/rme.11.45 · Cited by 7
Faradji, R. N., Monroy, K., Cure, P., Froud, T., Baidal, D., Pileggi, A., Messinger, S., Ricordi, C., & Alejandro, R. (2005) · Transplantation Proceedings · doi:10.1016/j.transproceed.2005.09.090 · Cited by 7
Deno, S., Takemoto, N., & Iwata, H. (2014) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.11.023 · Cited by 7
The concept of immunothrombosis in pancreas transplantation
Masset, C., Drillaud, N., Ternisien, C., Degauque, N., Gérard, N., Bruneau, S., Branchereau, J., Blancho, G., Mesnard, B., Brouard, S., et al. (2024) · American Journal of Transplantation · doi:10.1016/j.ajt.2024.11.025 · Cited by 8
Metadata
- Authors
- Moberg, L., Johansson, H., Lukinius, A., Berne, C., Foss, A., Källen, R., Østraat, Ø., Salmela, K., Tibell, A., Tufveson, G., Elgue, G., Ekdahl, K. N., Korsgren, O., & Nilsson, B.
- Affiliations
- Uppsala University (SE)
- Uppsala University Hospital (SE)
- University of Helsinki (FI)
- Corresponding author
- Nilsson, B
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 360
- Issue
- 9350
- Pages
- 2039-2045
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2158070939
- Cited by
- 568
- References
- 0
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 13 · 2023: 17 · 2022: 16 · 2021: 13 · 2020: 24 · 2019: 37 · 2018: 23 · 2017: 24 · 2016: 35 · 2015: 25 · 2014: 26 · 2013: 29 · 2012: 29
- FWCI
- 16.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Knut och Alice Wallenbergs Stiftelse
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- tissue factor, islet transplantation, type 1 diabetes, coagulation activation, islet damage, factor VIIa, islet endocrine cells, graft loss, insulin secretion
- MeSH terms
- Adult, Blood Cell Count, Diabetes Mellitus, Type 1, Female, Humans, Islets of Langerhans, Male, Middle Aged, Postoperative Complications, Precipitin Tests, Thromboplastin, Thrombosis, Islets of Langerhans Transplantation
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