Selection of a C5a receptor antagonist from phage libraries attenuating the inflammatory response in immune complex disease and ischemia reperfusion injury
T. Heller et al., Selection of a C5a receptor antagonist from phage libraries attenuating the inflammatory response in immune complex disease and ischemia reperfusion injury, J IMMUNOL, 163(2), 1999, pp. 985-994
A C5a-receptor antagonist was selected from human C5a phage display librari
es in which the C terminus of des-Arg(74)-hC5a was mutated. The selected mo
lecule is a competitive C5a receptor antagonist in vitro and in vivo. Signa
l transduction is interrupted at the level of G-protein activation. In addi
tion, the antagonist does not cause any C5a receptor phosphorylation, Proin
flammatory properties such as chemotaxis or lysosomal enzyme release of dif
ferentiated U937 cells, as well as C5a-induced changes in intracellular Ca2
+ concentration of murine peritoneal macrophages, are inhibited. The in viv
o efficacy was evaluated in three different animal models of immune complex
diseases in mice, i.e., the reverse passive Arthus reaction in the periton
eum, skin, and lung, The i.v. application of the C5a receptor antagonist ab
rogated polymorphonuclear neutrophil accumulation in peritoneum and markedl
y attenuated polymorphonuclear neutrophil migration into the skin and the l
ung, In a model of intestinal ischemia/reperfusion injury, i.v. administrat
ion of the C5a receptor antagonist decreased local and remote tissue injury
: bowel wall edema and hemorrhage as well as pulmonary microvascular dysfun
ction, These data give evidence that C5a is an important mediator triggerin
g the inflammatory sequelae seen in immune complex diseases and ischemia/re
perfusion injury. The selected C5a receptor antagonist may prove useful to
attenuate the inflammatory response in these disorders.