THE EFFECTS OF SOLUBLE RECOMBINANT COMPLEMENT RECEPTOR-1 ON COMPLEMENT-MEDIATED EXPERIMENTAL GLOMERULONEPHRITIS

Complement is a major mediator of tissue injury in several types of gl omerulonephritis. However, no therapeutic agents that inhibit compleme nt activation are available for human use. sCR1 (TP10, BRL 55736) is a recombinant, soluble human complement receptor 1 (CR1) molecule lacki ng transmembrane and cytoplasmic domains that inhibits C3 and C5 conve rtase activity by preferentially binding C4b and C3b. To test the effi cacy of sCR1 on complement-mediated glomerulonephritis, rats were pret reated with sCR1 (60 mg/kg per day) before and during the induction of three models of complement-dependent glomerulonephritis (concanavalin A and antithymocyte serum models of proliferative glomerulonephritis, passive Heymann nephritis). Daily sCR1 and complement hemolytic activ ity levels were measured, and renal histology and urine protein excret ion were examined. Mean serum sCR1 levels of 100 to 200 mu g/mL were m aintained with a reduction in complement hemolytic activity to less th an 15% in most animals. In the antithymocyte serum model, sCR1-treated animals had significant reductions in mesangiolysis, glomerular plate let and macrophage infiltrates, and proteinuria at 48 h. In the concan avalin A model, sCR1 significantly reduced glomerular C3 and fibrin de posits, platelet infiltrates, and proteinuria at 48 h. In passive Heym ann nephritis, proteinuria was also significantly reduced (199 +/- 8.5 versus 125 +/- 16 mg/day, P < 0.002) at 5 days. It was concluded that sCR1 significantly reduces both morphologic and functional consequenc es of several different types of complement-mediated glomerulonephriti s and deserves evaluation as a potential therapeutic agent in compleme nt-mediated immune glomerular disease in humans.