INVOLVEMENT OF BOTH THE CLASSICAL AND ALTERNATE PATHWAYS OF COMPLEMENT IN AN EX-VIVO MODEL OF XENOGRAFT REJECTION

Background. It is now generally accepted that complement activation is critical for the hyperacute rejection of xenografts. Activation of th e classical pathway as the result of the interaction of xenoreactive I gM xenoantibodies with the vascular endothelium has been observed in a ll species combinations examined to date. A number of studies using a variety of species combinations have also implicated alternate pathway involvement; however, these studies do not enable a conclusion to be drawn as to whether the alternate pathway can be activated in the comp lete absence of classical pathway activation. Methods. In this study, human plasma was depleted of both Clq and factor D and then reconstitu ted with purified Clq or factor D to restore the classical and alterna te complement pathways, respectively. The ability of these modified pl asmas to prosecute hyperacute rejection was then examined using an ex vivo isolated mouse heart perfusion model based on the Langendorff sys tem. Results and Conclusions. In the mouse to human species combinatio n, both the classical and alternate pathways of complement are indepen dently capable of initiating complement activation and mediating xenog raft rejection.