Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation

Masafumi Goto, Jenny Tjernberg, Denis Dufrane, Graciela Elgue, Daniel Brandhorst, Kristina Nilsson Ekdahl, Heidi Brandhorst, Lars Wennberg, Yoshimochi Kurokawa, Susumu Satomi, John D. Lambris, Pierre Gianello, Olle Korsgren, Bo Nilsson

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)225-234
Number of pages10
JournalXenotransplantation
Volume15
Issue number4
DOIs
Publication statusPublished - 2008

Keywords

  • Adult porcine islet
  • Compstatin
  • Instant blood-mediated inflammatory reaction
  • Low molecular weight dextran sulfate
  • Xenotransplantation

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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