Selection of a C5a receptor antagonist from phage libraries attenuating the inflammatory response in immune complex disease and ischemia/reperfusion injury.
A C5a-receptor antagonist was selected from human C5a phage display libraries in which the C terminus of des-Arg74-hC5a was mutated. The selected molecule is a competitive C5a receptor antagonist in vitro and in vivo. Signal transduction is interrupted at the level of G-protein activation. In addition, the antagonist does not cause any C5a receptor phosphorylation. Proinflammatory properties such as chemotaxis or lysosomal enzyme release of differentiated U937 cells, as well as C5a-induced changes in intracellular Ca2+ concentration of murine peritoneal macrophages, are inhibited. The in vivo efficacy was evaluated in three different animal models of immune complex diseases in mice, i.e., the reverse passive Arthus reaction in the peritoneum, skin, and lung. The i.v. application of the C5a receptor antagonist abrogated polymorphonuclear neutrophil accumulation in peritoneum and markedly attenuated polymorphonuclear neutrophil migration into the skin and the lung. In a model of intestinal ischemia/reperfusion injury, i.v. administration of the C5a receptor antagonist decreased local and remote tissue injury: bowel wall edema and hemorrhage as well as pulmonary microvascular dysfunction. These data give evidence that C5a is an important mediator triggering the inflammatory sequelae seen in immune complex diseases and ischemia/reperfusion injury. The selected C5a receptor antagonist may prove useful to attenuate the inflammatory response in these disorders.
Institute of Medical Microbiology, Department of Clinical Immunology, Department of Transplantation Surgery, Medical School Hannover, Germany.
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T
Heller
M
M
Hennecke
U
U
Baumann
J E
JE
Gessner
A M
AM
zu Vilsendorf
M
M
Baensch
F
F
Boulay
A
A
Kola
A
A
Klos
W
W
Bautsch
J
J
Köhl
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics; D001183:Arthus Reaction / Q000276:immunology / Q000473:pathology; D017104:Bacteriophage M13 / Q000235:genetics / Q000276:immunology*; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D015936:Complement C5a / Q000378:metabolism*; D005260:Female; D006801:Humans; D007105:Immune Complex Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000276:immunology; D019151:Peptide Library; D010538:Peritonitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D020298:U937 Cells
D015703:Antigens, CD; D019151:Peptide Library; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a