FUNCTIONAL-ACTIVITY OF ANTI-C6 ANTIBODIES ELICITED IN C6-DEFICIENT RATS RECONSTITUTED BY LIVER ALLOGRAFTS - ABILITY TO INHIBIT HYPERACUTE REJECTION OF DISCORDANT CARDIAC XENOGRAFTS

A critical role of the complement membrane attack complex (C5b-9) in m ediating hyperacute rejection has been demonstrated previously in full y C6-deficient PVG (C-) (RT1(c)) rats that reject guinea pig cardiac x enografts at a delayed tempo (45+/-9 hr; n=16) compared with C6-suffic ient PVG (C+) (RT1(c)) hosts (0.5+/-2 hr; n=6). We have investigated w hether selective depletion of C6 from Lewis rats by antibody therapy p revents hyperacute rejection. A polyclonal rat-antirat C6 antibody was induced in PVG (C-) recipients by orthotopic liver transplants from c ongenic PVG (C+) donors. These liver grafts produced high levels of C6 that reconstituted the complement function of PVG (C-) hosts by 7 day s, but the recipients responded within 28 days with the synthesis of a n IgG1 antibody to rat C6. The antiserum inhibited hemolytic complemen t activity of Lewis (RT1(1)) rats in vivo and in vitro. The effect of C6 depletion on Xg survival was investigated by injecting Lewis rats w ith 2 ml of rat-antirat C6 antiserum before and 1 ml after reperfusion of the guinea pig cardiac xenograft. Lewis rats rejected guinea pig c ardiac xenografts after treatment with this rat-antirat C6 antiserum i n 38+/-11 hr (n=3). Treatment with normal control sera from PVG (C-) r ats did not prolong guinea pig cardiac xenograft survival in the Lewis rats (1+/-0.7 hr; n=3) (P<0.0043). Injection of 3 ml of the IgG fract ion purified from the rat-antirat C6 antibody (33 mg/ml) prolonged xen ograft survival to 13.6+/-4 hr (n=4) compared with the survival of 0.6 1+/-0.3 hr (n=4) after injection of control rat IgG (33 mg/ml) (P<0.00 5). These results demonstrate that specific depletion of C6 by antibod y therapy has a significant effect on guinea pig cardiac xenograft sur vival in the Lewis rat. These findings further suggest that C6 depleti on may be beneficial to patients undergoing hyperacute rejection of xe nografts or allografts.