Natural killer cell-endothelial cell interactions in xenotransplantation

Interest in xenotransplantation derives from the documented need for more o rgans and tissues than can be expected from living or cadaveric donors, Alt hough the barriers to xenotransplantation are formidable, the scientific re wards in addressing these problems have been significant. The first and mos t potent barrier to xenotransplantation is hyperacute rejection mediated by xenoreactive natural antibodies and serum complement. The majority of the xenoreactive antibodies appear to be directed at terminal galactose epitope s, especially gal alpha1-3 gal. Significant progress has been made in surmo unting hyperacute rejection, and this has led to an examination of underlyi ng mechanisms of delayed xenograft rejection. One of these delayed mechanis ms concerns the potential role of graft recipient, natural killer (NK) cell s, NK cells can cause variable, low-level cytotoxicity of xenogeneic endoth elial cells in vitro that may be enhanced in the presence of xenoreactive I gG. The specificity of NK cell-mediated cytotoxicity appears to overlap wit h a major subset of xenoreactive natural antibodies. These cytotoxic intera ctions can be regulated by "humanizing" the endothelial cells through expre ssion of the appropriate human MHC class I genes. More important, NK cells induce endothelial cell activation, which results in changing the nature of the endothelial cell surface from an anticoagulant surface to a procoagula nt surface. These findings parallel those observed in allogeneic NK cell-en dothelial cell interactions and suggest these important observations may be extended to NK cell endothelial cell interactions in general.