Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts

Compstatin, a newly described C3-binding peptide, inhibits complement activ ation by blocking C3 convertase-mediated cleavage of C3. As the complement activation is an essential part of the rejection reaction, we evaluated the ability of Compstatin to delay or prevent hyperacute rejection in an ex vi vo xenograft model. Pig kidneys were perfused with fresh human blood contai ning either Compstatin (n=6) or a control agent (n=6). Graft survival and a ctivation of complement, leukocytes and platelets both in the fluid-phase a nd in the tissue were examined. The survival of the Compstatin-perfused kid neys (median, 380 min) was significantly (P=0.0036) longer than that of the controls (median, 90 min). The classical complement pathway (Clrs-Cl-inhib itor and C4bc) was significantly and equally activated in both groups durin g the first 60 min. C3 activation products increased fivefold and terminal complement complex eightfold in the control group, but Ilo increase occurre d in the Compstatin group during this period. Immunohistochemistry showed l ess C3 and fibrin deposition and immune electron microscopy showed less ter minal SC5b-9 complement complex deposition in the Compstatin group. A signi ficant change in total white cells, neutrophils, myeloperoxidase, and expre ssion of the surface activation markers CD11b (CR3) and CD35 (CR1) and CD62 L (L-selectin) was observed in both groups. Leukocyte activation was lower in the Compstatin group but the difference was not statistically significan t. There were no differences in platelet counts, thrombospondin, soluble P- selectin or P-thromboglobulin between the groups. We conclude that Compstat in prolongs graft survival and suggest that it may be a useful agent for at tenuating hyperacute rejection by inhibiting C3 and thus terminal complemen t pathway activation.