SELECTIVE-INHIBITION OF THE ALTERNATIVE COMPLEMENT PATHWAY BY SCR1[DESLHR-A] PROTECTS THE RABBIT ISOLATED HEART FROM HUMAN COMPLEMENT-MEDIATED DAMAGE

Evidence is presented that treatment with a selective inhibitor of the alternative complement pathway, sCR1[desLHR-A], protects the ex vivo perfused rabbit heart from human complement-mediated injury. Hearts fr om male New Zealand white rabbits were perfused in the Langendorff mod e. After equilibration, normal human plasma was added to the perfusate as a source of complement. Concomitant with the addition of human pla sma, vehicle (n = 13), soluble complement receptor type 1 (sCR1) (n = 10), or sCR1[desLHR-A], a truncated version of sCR1 that lacks the C4b binding region (n = 10) was included in the perfusate. Hemodynamic va riables were obtained for all groups before (baseline) and after the a ddition of human plasma. Compared to vehicle-treated hearts, variables recorded during perfusion with human plasma including coronary perfus ion pressure, left ventricular developed pressure, and left ventricula r end diastolic pressure, along with a reduction of creatine kinase ef flux, were improved in hearts perfused with either complement inhibito r. In addition, in vitro hemolysis assays were utilized to discriminat e between the classical and alternative pathways. The addition of sCR1 to human serum prevented both the classical and alternative pathway-m ediated hemolysis while sCR1[desLHR-A] prevented only the alternative pathway-mediated lysis. This study indicates that deletion of the C4b- binding site from sCR1 results in a new pharmacological moiety, sCR1[d esLHR-A], that primarily inhibits the alternative pathway of human com plement.