Effect of anticomplement agent K76 COOH on hamster-to-rat and guinea pig-to-rat heart xenotransplantation.
In normal rats, the xenobiotic K76 inhibited the C5 and probably the C2 and C3 steps of complement and effectively depressed classical complement pathway activity, alternative complement pathway activity, and the C3 complement component during and well beyond the drug's 3-hr half-life. It was tested alone and with intramuscular tacrolimus (TAC) and/or intragastric cyclophosphamide (CP) in rat recipients of heterotopic hearts from guinea pig (discordant) and hamster (concordant) donors. Single prevascularization doses of 100 and 200 mg/kg increased the median survival time of guinea pig hearts from 0.17 hr in untreated controls to 1.7 hr and 10.2 hr, respectively; with repeated injections of the 200-mg dose every 9-12 hr, graft survival time was increased to 18.1 hr. Pretreatment of guinea pig heart recipients for 10 days with TAC and CP, with or without perioperative splenectomy or infusion of donor bone marrow, further increased median graft survival time to 24 hr. Among the guinea pig recipients, the majority of treated animals died with a beating heart from respiratory failure that was ascribed to anaphylatoxins. Hamster heart survival also was increased with monotherapy using 200 mg/kg b.i.d. i.v. K76 (limited by protocol to 6 days), but only from 3 to 4 days. Survival was prolonged to 7 days with the addition of K76 of intragastric CP at 5 mg/kg per day begun 1 day before operation (to a limit of 9 days); it was prolonged to 4.5 days with the addition of intramuscular TAC at 2 mg/kg per day beginning on the day of transplantation and continued indefinitely. In contrast to the limited efficacy of the single drugs, or any two drugs in combination, the three drugs together (K76, CP, and TAC) in the same dose schedules increased median graft survival time to 61 days. Antihamster antibodies rapidly increased during the first 5 days after transplantation, and plateaued at an abnormal level in animals with long graft survival times without immediate humoral rejection. However, rejection could not be reliably prevented, and was present even in most of the xenografts recovered from most of the animals dying (usually from infection) with a beating heart. Thus, although effective complement inhibition with K76 was achieved in both guinea pig- and hamster-to-rat heart transplant models, the results suggest that effective interruption of the complement cascade will have a limited role, if any, in the induction of xenograft acceptance.
Tanaka
M
M
Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Murase
N
N
Ye
Q
Q
Miyazaki
W
W
Nomoto
M
M
Miyazawa
H
H
Manez
R
R
Toyama
Y
Y
Demetris
A J
AJ
Todo
S
S
Starzl
T E
TE
D000818:Animals; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D006224:Cricetinae; D003520:Cyclophosphamide / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D006168:Guinea Pigs; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D051381:Rats; D011917:Rats, Inbred Lew; D012717:Sesquiterpenes / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology; D014183:Transplantation, Heterologous / Q000276:immunology*
D003169:Complement Inactivator Proteins; D007166:Immunosuppressive Agents; D012717:Sesquiterpenes; C038797:K 76 carboxylic acid; D003520:Cyclophosphamide; D016559:Tacrolimus