Abstract

A discordant organ xenograft, such as a heart or kidney transplanted from pig to human, is rejected within 1 to 2 hours by a process called hyperacute rejection (HAR) caused in large or full measure by preexisting host xenoreactive natural antibodies (XNAs) and complement. HAR can be averted by blocking either complement or XNAs; but the xenograft is then rejected at 3 to 4 days by a process called delayed xenograft rejection (DXR), which can occur without the presence of T cells. DXR involves type II endothelial cell (EC) activation (the phase of activation that includes up-regulation of proinflammatory genes in the EC), infiltration into the graft of host monocytes and natural killer cells (both of which appear to be activated), and a complex cytokine picture. We discuss in this paper various approaches that might help prevent DXR, after which we assume that one would still have to deal with a xenograft counterpart of the T cell-mediated allograft rejection response. The approach to avoiding DXR focuses largely on genetic engineering of the ECs in the graft.