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 glomerulonephritis. However, no therapeutic agents that inhibit complement activation are available for human use. sCR1 (TP10, BRL 55736) is a recombinant, soluble human complement receptor 1 (CR1) molecule lacking transmembrane and cytoplasmic domains that inhibits C3 and C5 convertase activity by preferentially binding C4b and C3b. To test the efficacy of sCR1 on complement-mediated glomerulonephritis, rats were pretreated 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 Heyman nephritis). Daily sCR1 and complement hemolytic activity levels were measured, and renal histology and urine protein excretion were examined. Mean serum sCR1 levels of 100 to 200 micrograms/mL were maintained with a reduction in complement hemolytic activity to less than 15% in most animals. In the antithymocyte serum model, sCR1-treated animals had significant reductions in mesangiolysis, glomerular platelet and macrophage infiltrates, and proteinuria at 48 h. In the concanavalin A model, sCR1 significantly reduced glomerular C3 and fibrin deposits, platelet infiltrates, and proteinuria at 48 h. In passive Heymann 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 consequences of several different types of complement-mediated glomerulonephritis and deserves evaluation as a potential therapeutic agent in complement-mediated immune glomerular disease in humans.
Couser
W G
WG
Department of Medicine, University of Washington, Seattle, USA.
Johnson
R J
RJ
Young
B A
BA
Yeh
C G
CG
Toth
C A
CA
Rudolph
A R
AR
D000818:Animals; D000961:Antilymphocyte Serum; D003165:Complement System Proteins / Q000032:analysis / Q000276:immunology*; D003208:Concanavalin A / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000032:analysis; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011951:Receptors, Complement / Q000032:analysis; D011994:Recombinant Proteins / Q000032:analysis / Q000097:blood / Q000627:therapeutic use
D000961:Antilymphocyte Serum; D007074:Immunoglobulin G; D011951:Receptors, Complement; D011994:Recombinant Proteins; D003208:Concanavalin A; C082885:soluble complement inhibitor 1; D003165:Complement System Proteins