CRITICAL ROLE OF FAS FAS LIGAND INTERACTION IN CD28-INDEPENDENT PATHWAY OF ALLOGENEIC MURINE HEPATOCYTE REJECTION/

Cytolytic induction of T cells requires both the T-cell receptor (TCR) -mediated antigenic stimulation and the CD28-mediated co-stimulatory s ignal. Blockade of the interactions between CD28 and its ligands, CD80 and CD86, prolongs the survival of allografts in some transplantation models, However, we found that allogeneic hepatocytes were completely rejected within 7 days after intrasplenic transplantation, even when treated with monoclonal antibodies (mAbs) against CD80 and CD86 (anti- CD80/86), Recent studies have shown that there are two main mechanisms of T-cell-mediated cytotoxicity, perforin-based and Fas-based ones, I t has been shown that the liver is highly sensitive to induction of ap optosis by an agonistic anti-ras mAb. We then investigated the role of the Fas/Fas ligand (FasL) system in the CD28-independent allogeneic h epatocyte rejection. With the anti-CD80/86 mAb treatment, hepatocytes from C57BL/6 lpr/lpr (B6 lpr) mice, which express little Fas antigen, could survive for 7 days after intrasplenic transplantation, and hepat ocytes from C57BL/6 (B6) mice could also survive for 7 days in the spl een of C3H/ He gld/gld (C3H gld) mice, which express no functional Fas t. CD28-independent induction of cytotoxicity against allogeneic hepat ocytes was not observed when the effector cells were derived from C3H gld mice. These results indicated that the Fas/FasL system plays a cri tical role in the CD28-independent pathway of allogeneic hepatocyte re jection.