Sulfonated dextran inhibits complement activation and complement-dependent cytotoxicity in an in vitro model of hyperacute xenograft rejection.
In the present study, we demonstrate that a substituted soluble dextran derivative bearing 73% carboxylic groups and 15% benzylamide sulfonate groups, termed CMDBS25, inhibits complement activation and complement-mediated damage in an in vitro model of xenogeneic rejection. Incubation of porcine aortic endothelial cells with normal human serum resulted in time-dependent complement consumption as assessed by C3a generation in the fluid phase and deposition of activated complement fragments C3, C5 and of C5b-9 on target cells. The presence of C5b-9 membrane attack complex was associated with 51Cr release from prelabelled endothelial cells. The addition of 5-25 mg of CMDBS25/ml under the experimental conditions used, inhibited complement activation and C3a generation in a dose-dependent fashion. CMDBS25 (25 mg/ml) totally suppressed iC3b, C5 and C5b-9 cytolytic complex deposition on cells and inhibits by 42% lysis of target endothelial cells. Native dextran had no effect. Our observations document the anti-complementary properties of sulfonated dextran derivatives and their potential as therapeutic agents for the prevention of complement-dependent hyperacute xenograft rejection.
Thomas
H
H
INSERM U430, Hôpital Broussais, Paris, France.
Maillet
F
F
Letourneur
D
D
Jozefonvicz
J
J
Fischer
E
E
Kazatchkine
M D
MD
D000818:Animals; D001011:Aorta; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003911:Dextrans / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D003176:Complement C3; D003182:Complement C5; D003169:Complement Inactivator Proteins; D015938:Complement Membrane Attack Complex; D003911:Dextrans; C099253:CMDBS 25