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Olle Korsgren - One of the best experts on this subject based on the ideXlab platform.
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the instant blood mediated Inflammatory Reaction characterized in hepatocyte transplantation
Transplantation, 2011Co-Authors: Elisabet Gustafson, Graciela Elgue, Olle Korsgren, R D Hughes, Ragai R Mitry, Javier Sanchez, Ulf Haglund, Staffan Meurling, Anil Dhawan, Bo NilssonAbstract: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.
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low molecular weight dextran sulfate prevents the instant blood mediated Inflammatory Reaction induced by adult porcine islets
Transplantation, 2004Co-Authors: Masafumi Goto, Graciela Elgue, Olle Korsgren, Helena Johansson, Akira Maeda, Bo NilssonAbstract:Intraportal transplantation of isolated islets of Langerhans is a procedure approaching clinical acceptance as a treatment for patients with type I diabetes mellitus. One major problem with this treatment is that large amounts of cells are lost at the time of infusion into the portal vein, resulting in a low level of engraftment of the islets. One likely explanation for this loss is the instant blood-mediated Inflammatory Reaction (IBMIR), a thrombotic/Inflammatory Reaction occurring when islets come in contact with blood. The IBMIR is characterized by coagulation and complement activation, leading to platelet consumption, leukocyte infiltration of the islets, and disruption of islet integrity.In this thesis, the IBMIR is shown to be triggered by tissue factor (TF), the main initiator of blood coagulation in vivo. TF is expressed in two forms by the endocrine cells of the pancreas, a full-length membrane-bound and an alternatively spliced soluble form. Blocking TF in vitro efficiently reduces the macroscopic clotting, expression of coagulation activation markers, and leukocyte infiltration. This blockade can be achieved by adding either an active site-specific anti-TF antibody or site-inactivated FVIIa that competes with active FVIIa in the blood. TF may be secreted from the islets, since it is colocalized with insulin and glucagon in their granules. The IBMIR has also been demonstrated in vivo in patients transplanted with isolated islets.There are two ways to block the IBMIR in transplantation: systemic treatment of the patients, or islet pretreatment before transplantation to reduce their thrombogenicity. In this thesis, low molecular weight dextran sulfate (LMW-DS) is shown to reduce activation of the complement and coagulation systems and decrease the cell infiltration into the islets in vitro and in vivo, in both a xenogenic and an allogenic setting. Based on these results, LMW-DS is now in clinical trials.
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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
Diabetes, 2002Co-Authors: Lisa Ozmen, Kristina Nilsson Ekdahl, Graciela Elgue, Rolf Larsson, Olle Korsgren, Bo NilssonAbstract: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
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Isolated human islets trigger an instant blood mediated Inflammatory Reaction: Implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Islet transplantation offers a logical means to treat insulin-dependent diabetes. However, for reasons poorly understood, the clinical results with islet transplantation have been vastly inferior to those obtained with whole organ pancreas transplantation. The conventional technique for transplanting isolated islets is by intraportal injection, with the islets being trapped in the liver. Human islets exposed to human blood trigged an "instant blood mediated Inflammatory Reaction", IBMIR, characterised by platelet consumption, and activation of the coagulation and complement systems. The islets became surrounded by clots and infiltrated with leukocytes, and there was evidence of islet damage as reflected in insulin dumping. When heparin and a complement inhibitor (SCRI), was added to the system, IBMIR was suppressed and islet damage reduced. After intraportal pig-to-pig islet intraportal allotransplantation similar morphological changes was found, corroborating the in vitro findings. Thus, IBMIR inflicts a significant damage to human islets exposed to human blood and IBMIR will also, most likely, enhance the subsequent specific, cell mediated, rejection. Platelet and complement activation seem to be the most important factors in the pathogenesis of IBMIR. The results presented strongly suggest that IBMIR observed both in vitro and in vivo when isolated islets come in contact with blood could provide an explanation for the unsatisfactory results seen in clinical islet allotransplantation.
Bo Nilsson - One of the best experts on this subject based on the ideXlab platform.
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the instant blood mediated Inflammatory Reaction characterized in hepatocyte transplantation
Transplantation, 2011Co-Authors: Elisabet Gustafson, Graciela Elgue, Olle Korsgren, R D Hughes, Ragai R Mitry, Javier Sanchez, Ulf Haglund, Staffan Meurling, Anil Dhawan, Bo NilssonAbstract: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.
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low molecular weight dextran sulfate prevents the instant blood mediated Inflammatory Reaction induced by adult porcine islets
Transplantation, 2004Co-Authors: Masafumi Goto, Graciela Elgue, Olle Korsgren, Helena Johansson, Akira Maeda, Bo NilssonAbstract:Intraportal transplantation of isolated islets of Langerhans is a procedure approaching clinical acceptance as a treatment for patients with type I diabetes mellitus. One major problem with this treatment is that large amounts of cells are lost at the time of infusion into the portal vein, resulting in a low level of engraftment of the islets. One likely explanation for this loss is the instant blood-mediated Inflammatory Reaction (IBMIR), a thrombotic/Inflammatory Reaction occurring when islets come in contact with blood. The IBMIR is characterized by coagulation and complement activation, leading to platelet consumption, leukocyte infiltration of the islets, and disruption of islet integrity.In this thesis, the IBMIR is shown to be triggered by tissue factor (TF), the main initiator of blood coagulation in vivo. TF is expressed in two forms by the endocrine cells of the pancreas, a full-length membrane-bound and an alternatively spliced soluble form. Blocking TF in vitro efficiently reduces the macroscopic clotting, expression of coagulation activation markers, and leukocyte infiltration. This blockade can be achieved by adding either an active site-specific anti-TF antibody or site-inactivated FVIIa that competes with active FVIIa in the blood. TF may be secreted from the islets, since it is colocalized with insulin and glucagon in their granules. The IBMIR has also been demonstrated in vivo in patients transplanted with isolated islets.There are two ways to block the IBMIR in transplantation: systemic treatment of the patients, or islet pretreatment before transplantation to reduce their thrombogenicity. In this thesis, low molecular weight dextran sulfate (LMW-DS) is shown to reduce activation of the complement and coagulation systems and decrease the cell infiltration into the islets in vitro and in vivo, in both a xenogenic and an allogenic setting. Based on these results, LMW-DS is now in clinical trials.
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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
Diabetes, 2002Co-Authors: Lisa Ozmen, Kristina Nilsson Ekdahl, Graciela Elgue, Rolf Larsson, Olle Korsgren, Bo NilssonAbstract: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
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Isolated human islets trigger an instant blood mediated Inflammatory Reaction: Implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Islet transplantation offers a logical means to treat insulin-dependent diabetes. However, for reasons poorly understood, the clinical results with islet transplantation have been vastly inferior to those obtained with whole organ pancreas transplantation. The conventional technique for transplanting isolated islets is by intraportal injection, with the islets being trapped in the liver. Human islets exposed to human blood trigged an "instant blood mediated Inflammatory Reaction", IBMIR, characterised by platelet consumption, and activation of the coagulation and complement systems. The islets became surrounded by clots and infiltrated with leukocytes, and there was evidence of islet damage as reflected in insulin dumping. When heparin and a complement inhibitor (SCRI), was added to the system, IBMIR was suppressed and islet damage reduced. After intraportal pig-to-pig islet intraportal allotransplantation similar morphological changes was found, corroborating the in vitro findings. Thus, IBMIR inflicts a significant damage to human islets exposed to human blood and IBMIR will also, most likely, enhance the subsequent specific, cell mediated, rejection. Platelet and complement activation seem to be the most important factors in the pathogenesis of IBMIR. The results presented strongly suggest that IBMIR observed both in vitro and in vivo when isolated islets come in contact with blood could provide an explanation for the unsatisfactory results seen in clinical islet allotransplantation.
Rolf Larsson - One of the best experts on this subject based on the ideXlab platform.
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islet surface heparinization prevents the instant blood mediated Inflammatory Reaction in islet transplantation
Diabetes, 2007Co-Authors: Sanja Cabric, Javier Sanchez, Torbjorn Lundgren, Aksel Foss, Marie Felldin, Ragnar Kallen, Kaija Salmela, A Tibell, Gunnar Tufveson, Rolf LarssonAbstract:OBJECTIVE —In clinical islet transplantation, the instant blood-mediated Inflammatory Reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This Reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface. RESEARCH DESIGN AND METHODS —A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant. RESULTS —Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets. CONCLUSIONS —This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
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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
Diabetes, 2002Co-Authors: Lisa Ozmen, Kristina Nilsson Ekdahl, Graciela Elgue, Rolf Larsson, Olle Korsgren, Bo NilssonAbstract: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
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Isolated human islets trigger an instant blood mediated Inflammatory Reaction: Implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Islet transplantation offers a logical means to treat insulin-dependent diabetes. However, for reasons poorly understood, the clinical results with islet transplantation have been vastly inferior to those obtained with whole organ pancreas transplantation. The conventional technique for transplanting isolated islets is by intraportal injection, with the islets being trapped in the liver. Human islets exposed to human blood trigged an "instant blood mediated Inflammatory Reaction", IBMIR, characterised by platelet consumption, and activation of the coagulation and complement systems. The islets became surrounded by clots and infiltrated with leukocytes, and there was evidence of islet damage as reflected in insulin dumping. When heparin and a complement inhibitor (SCRI), was added to the system, IBMIR was suppressed and islet damage reduced. After intraportal pig-to-pig islet intraportal allotransplantation similar morphological changes was found, corroborating the in vitro findings. Thus, IBMIR inflicts a significant damage to human islets exposed to human blood and IBMIR will also, most likely, enhance the subsequent specific, cell mediated, rejection. Platelet and complement activation seem to be the most important factors in the pathogenesis of IBMIR. The results presented strongly suggest that IBMIR observed both in vitro and in vivo when isolated islets come in contact with blood could provide an explanation for the unsatisfactory results seen in clinical islet allotransplantation.
William Bennet - One of the best experts on this subject based on the ideXlab platform.
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Isolated human islets trigger an instant blood mediated Inflammatory Reaction: Implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
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isolated human islets trigger an instant blood mediated Inflammatory Reaction implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes
Upsala Journal of Medical Sciences, 2000Co-Authors: William Bennet, Rolf Larsson, Bo Nilsson, C G Groth, Olle KorsgrenAbstract:Islet transplantation offers a logical means to treat insulin-dependent diabetes. However, for reasons poorly understood, the clinical results with islet transplantation have been vastly inferior to those obtained with whole organ pancreas transplantation. The conventional technique for transplanting isolated islets is by intraportal injection, with the islets being trapped in the liver. Human islets exposed to human blood trigged an "instant blood mediated Inflammatory Reaction", IBMIR, characterised by platelet consumption, and activation of the coagulation and complement systems. The islets became surrounded by clots and infiltrated with leukocytes, and there was evidence of islet damage as reflected in insulin dumping. When heparin and a complement inhibitor (SCRI), was added to the system, IBMIR was suppressed and islet damage reduced. After intraportal pig-to-pig islet intraportal allotransplantation similar morphological changes was found, corroborating the in vitro findings. Thus, IBMIR inflicts a significant damage to human islets exposed to human blood and IBMIR will also, most likely, enhance the subsequent specific, cell mediated, rejection. Platelet and complement activation seem to be the most important factors in the pathogenesis of IBMIR. The results presented strongly suggest that IBMIR observed both in vitro and in vivo when isolated islets come in contact with blood could provide an explanation for the unsatisfactory results seen in clinical islet allotransplantation.
Graciela Elgue - One of the best experts on this subject based on the ideXlab platform.
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the instant blood mediated Inflammatory Reaction characterized in hepatocyte transplantation
Transplantation, 2011Co-Authors: Elisabet Gustafson, Graciela Elgue, Olle Korsgren, R D Hughes, Ragai R Mitry, Javier Sanchez, Ulf Haglund, Staffan Meurling, Anil Dhawan, Bo NilssonAbstract: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.
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dissecting the instant blood mediated Inflammatory Reaction in islet xenotransplantation
Xenotransplantation, 2008Co-Authors: Masafumi Goto, Kristina Nilsson Ekdahl, Graciela Elgue, Jenny Tjernberg, Denis Dufrane, D Brandhorst, H Brandhorst, Lars Wennberg, Yoshimochi Kurokawa, Susumu SatomiAbstract:BACKGROUND: A massive destruction of transplanted tissue occurs immediately following transplantation of pancreatic islets from pig to non-human primates. The detrimental instant blood-mediated Inflammatory Reaction (IBMIR), triggered by the porcine islets, is a likely explanation for this tissue loss. This Reaction may also be responsible for mediating an adaptive immune response in the recipient that requires a heavy immunosuppressive regimen. MATERIALS AND METHODS: Low molecular weight dextran sulfate (LMW-DS) and the complement inhibitor Compstatin were used in a combination of in vitro and in vivo studies designed to dissect the xenogeneic IBMIR in a non-human primate model of pancreatic islet transplantation. Adult porcine islets (10,000 IEQs/kg) were transplanted intraportally into three pairs of cynomolgus monkeys that had been treated with LMW-DS or heparin (control), and the effects on the IBMIR were characterized. Porcine islets were also incubated in human blood plasma in vitro to assess complement inhibition by LMW-DS and Compstatin. RESULTS: Morphological scoring and immunohistochemical staining revealed that the severe islet destruction and macrophage, neutrophilic granulocyte, and T-cell infiltration observed in the control (heparin-treated) animals were abrogated in the LMW-DS-treated monkeys. Both coagulation and complement activation were significantly reduced in monkeys treated with LMW-DS, but IgM and complement fragments were still found on the islet surface. This residual complement activation could be inhibited by Compstatin in vitro. CONCLUSIONS: The xenogeneic IBMIR in this non-human primate model is characterized by an immediate binding of antibodies that triggers deleterious complement activation and a subsequent clotting Reaction that leads to further complement activation. The effectiveness of LMW-DS (in vivo and in vitro) and Compstatin (in vitro) in inhibiting this IBMIR provides the basis for a protocol that can be used to abrogate the IBMIR in pig-human clinical islet transplantation.
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low molecular weight dextran sulfate prevents the instant blood mediated Inflammatory Reaction induced by adult porcine islets
Transplantation, 2004Co-Authors: Masafumi Goto, Graciela Elgue, Olle Korsgren, Helena Johansson, Akira Maeda, Bo NilssonAbstract:Intraportal transplantation of isolated islets of Langerhans is a procedure approaching clinical acceptance as a treatment for patients with type I diabetes mellitus. One major problem with this treatment is that large amounts of cells are lost at the time of infusion into the portal vein, resulting in a low level of engraftment of the islets. One likely explanation for this loss is the instant blood-mediated Inflammatory Reaction (IBMIR), a thrombotic/Inflammatory Reaction occurring when islets come in contact with blood. The IBMIR is characterized by coagulation and complement activation, leading to platelet consumption, leukocyte infiltration of the islets, and disruption of islet integrity.In this thesis, the IBMIR is shown to be triggered by tissue factor (TF), the main initiator of blood coagulation in vivo. TF is expressed in two forms by the endocrine cells of the pancreas, a full-length membrane-bound and an alternatively spliced soluble form. Blocking TF in vitro efficiently reduces the macroscopic clotting, expression of coagulation activation markers, and leukocyte infiltration. This blockade can be achieved by adding either an active site-specific anti-TF antibody or site-inactivated FVIIa that competes with active FVIIa in the blood. TF may be secreted from the islets, since it is colocalized with insulin and glucagon in their granules. The IBMIR has also been demonstrated in vivo in patients transplanted with isolated islets.There are two ways to block the IBMIR in transplantation: systemic treatment of the patients, or islet pretreatment before transplantation to reduce their thrombogenicity. In this thesis, low molecular weight dextran sulfate (LMW-DS) is shown to reduce activation of the complement and coagulation systems and decrease the cell infiltration into the islets in vitro and in vivo, in both a xenogenic and an allogenic setting. Based on these results, LMW-DS is now in clinical trials.
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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
Diabetes, 2002Co-Authors: Lisa Ozmen, Kristina Nilsson Ekdahl, Graciela Elgue, Rolf Larsson, Olle Korsgren, Bo NilssonAbstract: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