Methotrexate for immunosuppression in life-supporting pig-to-cynomolgus monkey renal xenotransplantation.
Methotrexate (MTX) has been used successfully as an immunosuppressant in rodent xenotransplantation models, but the data generated so far with MTX in pig-to-baboon cardiac transplantation studies have been disappointing. The potential of this agent was consequently explored in a life-supporting pig-to-primate renal model using the cynomolgus monkey as the recipient species. Introductory in vitro and in vivo pharmacokinetic and pharmacodynamic studies with MTX were conducted in three cynomolgus monkeys. Subsequently, 10 cynomolgus monkey recipients of a life-supporting kidney from human decay-accelerating factor transgenic pigs were administered MTX intravenously according to three different regimens. All the animals also received cyclosporine A and steroids. In addition, mycophenolate sodium (MPS) was administered post-operatively in two of the three groups of transplanted animals. At clinically relevant concentrations, MTX is able in vitro to inhibit the mixed lymphocyte reactions (MLR) in cynomolgus monkeys. After intravenous administration, moreover, exposure of cynomolgus monkeys to MTX appeared to be higher than had been previously reported in baboons. Graft function was observed in the transplanted animals, which survived from 0 to 41 days. All but two animals revealed acute humoral rejection in the explanted graft and developed diarrhea. Diarrhea was the cause of euthanasia in five cases. It was unrelated to the administration of MPS and associated with severe histopathological signs of enteritis. This study demonstrates that the pharmacokinetic and pharmacodynamic profiles if MTX vary substantially between non-human primate species. In vitro, MTX has immunosuppressive properties in the cynomolgus monkey at clinically relevant concentrations. In vivo, MTX has a very narrow therapeutic window in cynomolgus monkeys, however, as it does in baboons. We conclude that MTX is scarcely effective as an immunosuppressant, be it for induction or maintenance, in pig-to-cynomolgus monkey renal xenotransplantation.
Cozzi
Emanuele
E
Direzione Sanitaria, Padua General Hospital, Padua, Italy.
Cadrobbi
Roberto
R
Baldan
Nicola
N
Dedja
Arben
A
Calabrese
Fiorella
F
Castagnaro
Massimo
M
Fante
Fabio
F
Boldrin
Massimo
M
Iacopetti
Ilaria
I
Ravarotto
Licia
L
Carraro
Paolo
P
Bronte
Vincenzo
V
De Santo
Carmela
C
Busetto
Roberto
R
Plebani
Mario
M
Cancellotti
Francesco Maria
FM
Rigotti
Paolo
P
Thiene
Gaetano
G
Ancona
Ermanno
E
D000818:Animals; D030801:Animals, Genetically Modified; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D013552:Swine; D014183:Transplantation, Heterologous
D018958:CD55 Antigens; D007166:Immunosuppressive Agents; D008727:Methotrexate