INHIBITION OF THE CLASSICAL AND ALTERNATIVE PATHWAYS OF THE HUMAN-COMPLEMENT SYSTEM BY GLYCOSAMINOGLYCAN POLYSULFATE

Glycosaminoglycan polysulfate (GAGPS) concentration-dependently inhibi ted the activation of the classical and alternative pathways of the hu man complement system in vitro. Concentrations of greater-than-or-equa l-to 0.2 mg/ml GAGPS prevented the cleavage of C4 by human aggregated gammaglobulin as evidence of inhibition of the classical pathway. At c oncentrations of greater-than-or-equal-to 0.15 mg/ml a concentration-d ependent inhibition of the cleavage of factor B, the major step in the activation of the alternative pathway, was seen in the presence of in ulin. Concentrations <0.05 mg/ml did not have a measurable effect on e ither pathway. The lysis of sheep red blood cells, which is mediated l argely by the classical pathway, was significantly inhibited at 3.84 m g/ml GAGPS, with a mean inhibition of 45.7%. On the other hand, the sa me concentration of GAGPS almost completely inhibited the lysis of rab bit red blood cells, which is mediated by the alternative pathway of c omplement. Our results suggest that the inhibition by GAGPS is an earl y event in the activation of complement, occurring before the assembly of the C3 convertases of either pathway. The possible use of this dru g in acute life-threatening situations where complement is thought to have a pathogenic role is discussed.