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Dissecting the instant blood‐mediated inflammatory reaction in islet xenotransplantation

Dissecting the instant blood‐mediated inflammatory reaction in islet xenotransplantation 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Xenotransplantation Wiley

Dissecting the instant blood‐mediated inflammatory reaction in islet xenotransplantation

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References (30)

Publisher
Wiley
Copyright
© 2008 Wiley Periodicals, Inc.
ISSN
0908-665X
eISSN
1399-3089
DOI
10.1111/j.1399-3089.2008.00482.x
pmid
18957045
Publisher site
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Abstract

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.

Journal

Xenotransplantation – Wiley

Published: Jul 1, 2008

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