Soluble Human Complement Receptor Type 1: In Vivo Inhibitor of Complement Suppressing Post-Ischemic Myocardial Inflammation and Necrosis

Abstract

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.

sCR1sLeX reduces lung allograft ischemia–reperfusion injury but does not ameliorate acute rejection

“…Ischemia-reperfusion injury has been shown to be complement dependent, because inhibitors of complement activation limited this type of injury, e.g. in models of rat myocardial infarction [12], acute neutrophil dependent inflammatory lung injury [13] or iso-and allograft transplantation [14,15]. In rat lung isotransplantation, sCR1 conferred protection against lung injury.…”

Baculovirus-mediated gene transfer in the presence of human serum or blood facilitated by inhibition of the complement system

“…Depletion of the C system is feasible by application of antibodies directed against distinct C components or CVF (this study). Furthermore, the use of soluble C receptors 38 (sCR1) for inhibition of the C cascade could support baculovirusmediated gene transfer in vivo. Exclusion of the C system seems to be likely by in situ perfusion methods, which have already been carried out in the course of retrovirusmediated gene transfer into the liver in vivo.…”

Effect of Soluble Complement Receptor-1 on Neutrophil Accumulation after Traumatic Brain Injury in Rats

“…sCRI is effective in rats and humans and protects in models of inflam mation outside the CNS. Weisman et al (1990) ad ministered sCRI to rats immediately before coro nary artery ligation. In myocardial specimens of the area at risk (3 h after reperfusion), complement ac tivation was suppressed to undetectable levels, and leukocyte accumulation was decreased by 66%.…”