Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation.
Recently, a C3-binding cyclic synthetic peptide (Compstatin) has been identified that binds to complement component C3 and inhibits complement activation. Here we have examined the influence of Compstatin on complement activation and its indirect effects on cellular responses in whole blood in two models for extracorporeal circulation. Compstatin effectively inhibited the generation of C3a and sC5b-9 and the binding of C3/ C3 fragments to the polymer surface. As a result of the inhibition of complement activation, the activation of polymorphonuclear leukocytes (PMNs; as assessed by the expression of CD11b) and the binding of these cells (CD16(+)) to the polymer surface were almost completely lost. In contrast, blood cell counts were not affected. Using surface plasmon resonance technology, we have confirmed that Compstatin exerts its inhibitory effect on complement activation by binding to native C3. These data show that complement activation, leading to activation and binding of PMNs to the biomaterial surface, can be abolished by the addition of Compstatin. The properties of Compstatin make Compstatin a promising drug for use in extracorporeal circuits to avoid bioincompatibility reactions, eg, during cardiopulmonary bypass, but also a favorable precursor peptide for the development of an anticomplement drug for oral use.
Nilsson
B
B
Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
Larsson
R
R
Hong
J
J
Elgue
G
G
Ekdahl
K N
KN
Sahu
A
A
Lambris
J D
JD
D000595:Amino Acid Sequence; D018845:CD11 Antigens / Q000032:analysis; D003176:Complement C3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors; D003170:Complement Pathway, Alternative / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005112:Extracorporeal Circulation; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011108:Polymers; D017452:Receptors, IgG / Q000032:analysis
D018845:CD11 Antigens; D003176:Complement C3; D003169:Complement Inactivator Proteins; D015938:Complement Membrane Attack Complex; D010456:Peptides, Cyclic; D011108:Polymers; D017452:Receptors, IgG; C111828:compstatin