C1-Inhibitor for treatment of acute vascular xenograft rejection in cynomolgus recipients of h-DAF transgenic porcine kidneys.
At present, the major barrier to successful discordant xenotransplantation of unmodified or complement regulator transgenic porcine xenografts is acute vascular xenograft rejection (AVR). AVR is associated with the intragraft deposition of induced recipient xenoreactive antibodies and subsequent complement activation. In a life-supporting pig to primate kidney xenotransplantation setting using h-DAF transgenic donor organs and postoperative immunosuppression, episodes of AVR were either treated with boluses of cyclophosphamide and steroids or with the same regimen supplemented by a three-day course of C1-Inhibitor, a multifunctional complement regulator. In 8 out of 10 animals stable initial graft function was achieved; in all animals one or more episodes of AVR were observed. When, in 4 animals, C1-Inhibitor was added to the standard anti-rejection treatment regimen, AVR was successfully reversed in 6 out of 7 episodes, while in another group of 4 animals receiving the standard anti-rejection treatment 0 out of 4 episodes of AVR responded to treatment. Response to anti-rejection treatment was associated with a significant increase in recipient survival time. We conclude that AVR of h-DAF transgenic porcine kidneys can be successfully treated by additional short-term fluid phase complement inhibition.
Vangerow
B
B
Department of Anesthesiology, Hannover Medical School, D-30625 Hannover, Germany.
Hecker
J M
JM
Lorenz
R
R
Loss
M
M
Przemeck
M
M
Appiah
R
R
Schmidtko
J
J
Jalali
A
A
Rueckoldt
H
H
Winkler
M
M
D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000276:immunology*; D018958:CD55 Antigens / Q000235:genetics / Q000502:physiology*; D003167:Complement Activation / Q000187:drug effects; D003520:Cyclophosphamide / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000098:blood supply*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D008775:Methylprednisolone / Q000627:therapeutic use; D011239:Prednisolone / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
D000910:Antibodies, Heterophile; D018958:CD55 Antigens; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D015842:Serine Proteinase Inhibitors; D016572:Cyclosporine; D003520:Cyclophosphamide; D011239:Prednisolone; D008775:Methylprednisolone