Prolonging discordant xenograft survival with anticomplement reagents K76COOH and FUT175.
The guinea pig heart, when transplanted into the rat heterotopically, is rejected within 30 min via activation of the alternative complement pathway. Natural antibody does not contribute to rejection. This xenotransplantation model was used to assess the effect of anti-complement reagents on discordant xenograft survival. In vivo administration of K76COOH (K76) to rats induced only slight suppression of factors B and D and a marked decrease of C3, leading to the depression of ACH50 (reflecting the potency of the alternative pathway). On the other hand, FUT175 (FUT) reduced C3 activity by about 80% and inhibited factor B activity nearly 100% < 1 hr after the administration, but inhibited factor D activity only marginally. FUT abrogated ACH50 for > 6 hr. Of note, the xenograft beating time was prolonged approximately 3 times by FUT but not by K76, suggesting that direct inhibition of plasma serine protease factor B results in the complete suppression of ACH50 and graft survival. The administration of both K76 and FUT resulted in the longest graft survival, but the effects of these reagents were abolished by additional antigraft antibody. Anticomplement reagents that block factor B and C3 are therefore effective for prolongation of discordant xenograft survival when the graft rejection is associated with the complement alternative pathway.
Miyagawa
S
S
First Department of Surgery, Osaka University Medical School, Japan.
Shirakura
R
R
Matsumiya
G
G
Fukushima
N
N
Nakata
S
S
Matsuda
H
H
Matsumoto
M
M
Kitamura
H
H
Seya
T
T
D000818:Animals; D001550:Benzamidines; D003176:Complement C3 / Q000032:analysis; D011415:Complement Factor B / Q000032:analysis; D011416:Complement Factor D / Q000032:analysis; D003169:Complement Inactivator Proteins / Q000627:therapeutic use*; D003170:Complement Pathway, Alternative; D003165:Complement System Proteins / Q000032:analysis; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D006146:Guanidines / Q000627:therapeutic use*; D006168:Guinea Pigs; D016027:Heart Transplantation / Q000276:immunology; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012717:Sesquiterpenes / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
D001550:Benzamidines; D003176:Complement C3; D003169:Complement Inactivator Proteins; D006146:Guanidines; D012717:Sesquiterpenes; C038797:K 76 carboxylic acid; D003165:Complement System Proteins; D011416:Complement Factor D; D011415:Complement Factor B; C032855:nafamostat