Effects of complement inhibition with soluble complement receptor-1 on vascular injury and inflammation during renal allograft rejection in the rat.
Complement is both an effector of the humoral immune response and a stimulator of leukocyte activation. To examine the influence of complement on the allograft response, we inhibited complement using recombinant human soluble complement receptor-1 (sCR1; TP10), in an unsensitized model of rat renal allograft rejection. Lewis to DA renal transplant recipients were treated daily with 25 mg/kg sCR1 or saline and sacrificed on days 1 to 5 after transplant. Transplanted organs were examined histologically and immunohistochemically for leukocyte subset markers and for the third component of complement, C3, and membrane attack complex deposition. A second set of recipients was followed from day 5 to day 9 to assess graft survival. sCR1-treated recipients displayed > 90% inhibition of plasma complement activity and a marked reduction in tissue C3 and membrane attack complex deposition. Inactivation of complement reduced the vascular injury such that there was almost complete sparing of vascular damage in day 5 sCR1-treated rats. There was a significant reduction in infiltrating leukocytes by day 5 after transplant, and complement inhibition delayed the time to reach a histologically defined end point of graft survival from 5 days in controls to 9 days in the sCR1-treated group. These results imply that the vascular and cell-mediated injury arises, in part, from complement activation. The partial inhibition of these injuries by sCR1 may have functional implications for strategies to inhibit allograft rejection.
Pratt
J R
JR
Department of Nephrology, Guy's Hospital, London, United Kingdom, UK.
Hibbs
M J
MJ
Laver
A J
AJ
Smith
R A
RA
Sacks
S H
SH
D000208:Acute Disease; D000818:Animals; D003176:Complement C3 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000276:immunology* / Q000494:pharmacology; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology*; D006084:Graft Rejection / Q000473:pathology* / Q000503:physiopathology; D006085:Graft Survival; D007511:Ischemia / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology*; D007700:Kinetics; D007962:Leukocytes / Q000145:classification; D051381:Rats; D011917:Rats, Inbred Lew; D011951:Receptors, Complement / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D012995:Solubility; D014184:Transplantation, Homologous
D003176:Complement C3; D003169:Complement Inactivator Proteins; D015938:Complement Membrane Attack Complex; D011951:Receptors, Complement