Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes

We investigated the pathogenesis of chronic allograft rejection in mouse ca rdiac allografts. Long-term survival occurred after administration of monoc lonal antibody to CD4 or CD40-ligand (CD40L) plus donor cells. Both treatme nts induced permanent graft survival, but, in contrast to transplants in mi ce treated with CD4 monoclonal antibody, grafts in mice treated with CD40L monoclonal antibody lacked evidence of chronic rejection, including transpl ant arteriosclerosis, Freedom from chronic rejection in the group treated w ith CD IOL monoclonal antibody correlated with vascular expression of the ' protective' genes heme oxygenase-1 (HO-1), Bcl-xL and A20. Moreover, arteri osclerosis was induced in allografts in immunoglobulin-deficient mice by an tibody transfer only when the transfer was done before expression of protec tive genes. A direct role for protective gene expression in endothelial cel ls was demonstrated by in vitro experiments in which induction of HO-1 or B cl-xL suppressed alloantibody-stimulated endothelial activation. Finally, i nduction of HO-1 in vivo protected allografts against chronic injury. These data show a role for protective genes in the prevention of chronic rejecti on, and indicate new approaches to protect grafts against development of tr ansplant arteriosclerosis.