C1-inhibitor for prophylaxis of xenograft rejection after pig to cynomolgus monkey kidney transplantation.
BACKGROUND
Early rejection of discordant porcine xenografts in primate recipients is initiated by the intragraft binding of either preformed (hyperacute xenograft rejection) or induced (acute vascular rejection) antiporcine recipient antibodies with subsequent complement activation via the classical pathway. We have investigated the efficacy of the supplemental administration of C1-inhibitor (C1-INH), a specific inhibitor of the classical complement activation pathway, for prophylaxis of xenograft rejection in a pig to primate kidney xenotransplantation setting.


METHODS
Based on the results of pharmacokinetic studies performed in two nontransplanted monkeys, supplemental C1-INH therapy was administered daily to three Cynomolgus monkeys receiving a life-supporting porcine kidney transplant together with cyclophosphamide-induction/cyclosporine A/mycophenolat-mofetil/steroid immunosuppressive therapy.


RESULTS
In the three monkeys receiving porcine kidney xenografts and continuous C1-INH treatment none of the grafts underwent hyperacute rejection; all xenografts showed initial function. Recipient survival was 13, 15, and 5 days. No graft was lost due to acute vascular rejection. All animals died with a functioning graft (latest creatinine 96, 112, and 96 micromol/liter) due to bacterial septicemia.


CONCLUSIONS
We conclude that, in our model, supplemental C1-INH therapy together with a standard immunosuppressive regimen can be helpful for prevention of xenograft rejection in a pig to primate kidney xenotransplantation setting. The optimal dose and duration of C1-INH treatment, however, has yet to be determined.
Hecker
Jens M
JM
Klinik für Viszeral- und Transplantationschirurgie, Zentrum Anästhesiologie, Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany.
Lorenz
Ralf
R
Appiah
Richard
R
Vangerow
Burkhard
B
Loss
Martin
M
Kunz
Robert
R
Schmidtko
Jan
J
Mengel
Michael
M
Klempnauer
Jürgen
J
Piepenbrock
Siegfried
S
Dickneite
Gerhard
G
Neidhardt
Helge
H
Rückoldt
Horst
H
Winkler
Michael
M
D000208:Acute Disease; D000818:Animals; D003174:Complement C1 Inactivator Proteins / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D003174:Complement C1 Inactivator Proteins; D007166:Immunosuppressive Agents