TY - JOUR
T1 - Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation
AU - Goto, Masafumi
AU - Tjernberg, Jenny
AU - Dufrane, Denis
AU - Elgue, Graciela
AU - Brandhorst, Daniel
AU - Ekdahl, Kristina Nilsson
AU - Brandhorst, Heidi
AU - Wennberg, Lars
AU - Kurokawa, Yoshimochi
AU - Satomi, Susumu
AU - Lambris, John D.
AU - Gianello, Pierre
AU - Korsgren, Olle
AU - Nilsson, Bo
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - Adult porcine islet
KW - Compstatin
KW - Instant blood-mediated inflammatory reaction
KW - Low molecular weight dextran sulfate
KW - Xenotransplantation
UR - http://www.scopus.com/inward/record.url?scp=50949096307&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=50949096307&partnerID=8YFLogxK
U2 - 10.1111/j.1399-3089.2008.00482.x
DO - 10.1111/j.1399-3089.2008.00482.x
M3 - Article
C2 - 18957045
AN - SCOPUS:50949096307
SN - 0908-665X
VL - 15
SP - 225
EP - 234
JO - Xenotransplantation
JF - Xenotransplantation
IS - 4
ER -