Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis.
The complement system is an important mediator of the acute inflammatory response, and an effective inhibitor would suppress tissue damage in many autoimmune and inflammatory diseases. Such an inhibitor might be found among the endogenous regulatory proteins of complement that block the enzymes that activate C3 and C5. Of these proteins, complement receptor type 1 (CR1; CD35) has the most inhibitory potential, but its restriction to a few cell types limits its function in vivo. This limitation was overcome by the recombinant, soluble human CR1, sCR1, which lacks the transmembrane and cytoplasmic domains. The sCR1 bivalently bound dimeric forms of its ligands, C3b and methylamine-treated C4 (C4-ma), and promoted their inactivation by factor I. In nanomolar concentrations, sCR1 blocked complement activation in human serum by the two pathways. The sCR1 had complement inhibitory and anti-inflammatory activities in a rat model of reperfusion injury of ischemic myocardium, reducing myocardial infarction size by 44 percent. These findings identify sCR1 as a potential agent for the suppression of complement-dependent tissue injury in autoimmune and inflammatory diseases.
Weisman
H F
HF
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Bartow
T
T
Leppo
M K
MK
Marsh
H C
HC
Carson
G R
GR
Concino
M F
MF
Boyle
M P
MP
Roux
K H
KH
Weisfeldt
M L
ML
Fearon
D T
DT
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation; D003176:Complement C3 / Q000037:antagonists & inhibitors; D003180:Complement C3b Inactivator Proteins / Q000494:pharmacology; D015935:Complement C4b / Q000037:antagonists & inhibitors; D003182:Complement C5 / Q000037:antagonists & inhibitors; D003169:Complement Inactivator Proteins / Q000494:pharmacology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis; D051381:Rats; D011951:Receptors, Complement / Q000494:pharmacology* / Q000648:ultrastructure; D011994:Recombinant Proteins / Q000494:pharmacology
D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D003182:Complement C5; D003169:Complement Inactivator Proteins; D011951:Receptors, Complement; D011994:Recombinant Proteins; D015935:Complement C4b