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- Goto, Masafumi, et al.
(author)
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Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation
- 2008
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In: Xenotransplantation. - : Wiley. - 0908-665X .- 1399-3089. ; 15:4, s. 225-234
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Journal article (peer-reviewed)abstract
- 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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- Tokodai, Kazuaki, et al.
(author)
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Attenuation of Cross-Talk Between the Complement and Coagulation Cascades by C5a Blockade Improves Early Outcomes After Intraportal Islet Transplantation
- 2010
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In: Transplantation. - 0041-1337 .- 1534-6080. ; 90:12, s. 1358-1365
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Journal article (peer-reviewed)abstract
- Background. Complement 5a factor (C5a) elicits a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. C5a is also linked to the coagulant activity in autoimmune diseases. Therefore, C5a most likely plays a crucial role in the instant blood-mediated inflammatory reaction. Methods. Intraportal transplantation of 2.5 islet equivalents/g of syngeneic rat islet grafts was performed in two groups of streptozotocin-induced diabetic rats: controls and C5a inhibitory peptide (C5aIP)-treated group. Results. The thrombin-antithrombin complex was significantly suppressed in the C5aIP group (P = 0.003), and both the curative rate and the glucose tolerance were significantly improved in the C5aIP group (P < 0.05 and P < 0.005, respectively). Expression of tissue factor on granulocytes in recipient livers was up-regulated 1 h after islet infusion (P < 0.0001), which was significantly suppressed by C5aIP (P < 0.005). However, C5aIP was unable to regulate tissue factor expression on isolated islets. Furthermore, no differences were detected between the groups, regarding infiltration of CD11b-positive cells and deposition of C5b-9 on the islet grafts. Conclusions. These data suggest that C5aIP attenuates cross-talk between the complement and coagulation cascades through suppressing up-regulation of tissue factor expression on leukocytes in recipient livers but not on islet grafts, a process leading to improvement in islet engraftment. Therefore, C5aIP in combination with conventional anticoagulants could be a strong candidate strategy to control the instant blood-mediated inflammatory reaction induced in clinical islet transplantation.
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