HUMAN TRANSPLANT CORONARY-ARTERY DISEASE - PATHOLOGICAL EVIDENCE FOR FAS-MEDIATED APOPTOTIC CYTOTOXICITY IN ALLOGRAFT ARTERIOPATHY

Cytotoxicity mediated by cytolytic T cells occurs exclusively through Fas- and perforin-based pathways. Such mechanisms may be important in transplant coronary artery disease (TxCAD). We studied Fas and perfori n expression and apoptosis using immunohistochemical methods, in situ terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeli ng (TUNEL), and morphologic analysis of vessels with TxCAD taken from 12 transplant patients, which we compared with vessels of 10 patients with native coronary artery disease (CAD) and vessels from 14 patients with normal coronary arteries. Fas was detected in all TxCAD specimen s. Fas-positive cells were mainly endothelial cells (EC); 100% of EC a nd approximately one-third of T cells and macrophages were positive fo r Fas. Almost all TUNEL-positive cells were Fas-expressing cells. Of t he T cells and macrophages that expressed Fas, 18% appeared apoptotic in the mild and moderate-to-severe TxCAD group as compared with 78% in severe TxCAD patients (p = 0.0124). By contrast, EC damage was less e vident in the vessels with greater intimal disease severity: 10% in se vere TxCAD versus 75% in the mild and moderate-to-severe TxCAD group ( p = 0.0122). Perforin was positive in 5% of the total intimal T cells in 3 of 12 arteriopathy specimens. Fas and perforin were virtually neg ative in vessels taken from CAD patients. TUNEL was diffusely positive in CD68-positive foam cells in the lipid-rich core, but Fas was negat ive in all CAD specimens. In normal arteries, 8 of 14 specimens contai ned a few TUNEL-positive and Fas-positive EC and T cells. Perforin was negative. We conclude that EC damage in TxCAD seems to be brought abo ut through a Fas-based apoptotic pathway and that CD4-positive cytolyt ic T cells may be the major lytic cells involved in TxCAD.