Cytolytic induction of T cells requires both the T-cell recep-munosuppression, allogeneic hepatocytes were rapidly rejected within a few days after transplantation. 3 tor (TCR)-mediated antigenic stimulation and the CD28-mediated co-stimulatory signal. Blockade of the interactions be-
The rejection of allografts is dependent on the activation of alloreactive T cells, which requires T-cell receptor (TCR) tween CD28 and its ligands, CD80 and CD86, prolongs the survival of allografts in some transplantation models. How-engagement by antigen and co-stimulatory signals delivered by some T-cell surface molecules. 4 Signaling through the ever, we found that allogeneic hepatocytes were completely rejected within 7 days after intrasplenic transplantation, even TCR alone without a co-stimulatory signal induces a state of T-cell anergy. Blockade of co-stimulatory signal is useful when treated with monoclonal antibodies (mAbs) against CD80 and CD86 (anti-CD80/86). Recent studies have shown for transplantation. [10] Most particularly interesting co-stimulatory molecules are CD80 and CD86, which interact with that there are two main mechanisms of T-cell-mediated cytotoxicity, perforin-based and Fas-based ones. It has been shown their receptor (CD28) on T cells to provide a key signal for generation of T-cell immunity. 11 Activation of the TCR in that the liver is highly sensitive to induction of apoptosis by an agonistic anti-Fas mAb. We then investigated the role of the presence of a co-stimulatory signal from CD28 results in T-cell clonal expansion and the induction of effector func-the Fas/Fas ligand (FasL) system in the CD28-independent allogeneic hepatocyte rejection. With the anti-CD80/86 mAb tions such as the production of lymphokines and the induction of cytotoxic activity. 12 Consequently, blockade of the treatment, hepatocytes from C57BL/6 lpr/lpr (B6 lpr) mice, which express little Fas antigen, could survive for 7 days after CD28 co-stimulatory pathway by the treatment with anti-CD80/86 monoclonal antibody (mAb) or CTLA4 Immuno-intrasplenic transplantation, and hepatocytes from C57BL/6 (B6) mice could also survive for 7 days in the spleen of C3H/ globulin (CTLA4-Ig), which is a fusion protein comprising the extracellular domain of CTLA4 and the Fc domain of He gld/gld (C3H gld) mice, which express no functional FasL. CD28-independent induction of cytotoxicity against alloge-immunoglobulin G1 and binds to CD80/CD86, has been shown to prolong allograft survival in some transplantation neic hepatocytes was not observed when the effector cells were derived from C3H gld mice. These results indicated models. 10 Fas is type I membrane protein in the tumor necrosis factor that the Fas/FasL system plays a critical role in the CD28independent pathway of allogeneic hepatocyte rejection. (HEPreceptor superfamily and mediates apoptosis upon ligatation by an agonistic anti-Fas mAbs or its ligand (FasL) bind-ATOLOGY 1997;26:944-948.)
ing. 13,14 Molecular cloning of FasL revealed that it is a type II transmembrane protein and belongs to the tumor necrosis Hepatocyte transplantation has been expected to be a pofactor family. 15 It has been shown that there are two main tential therapeutic modality for congenital hepatic enzyme mechanisms of T-cell-mediated cytotoxicity, perforindeficiency or acute hepatic failure. The advantages of hepabased 16 and Fas-based ones. [17][19] The Fas/FasL system is tocyte transplantation over liver transplantation are as folthought to play an important role not only in T-and Blows: 1) it requires no vascular anastomosis; 2) long-term lymphocyte homeostasis, but also in T-cell-mediated cytopreservation of hepatocytes is possible; 3) gene therapy can toxicity. Hepatocytes are extremely sensitive to the Fasbe easily applied; and 4) hepatocytes can be transplanted to mediated apoptosis, because intraperitoneal injection of an several recipients from a single donor. We previously found agonistic anti-Fas mAb-induced apoptosis of hepatocytes that syngeneic hepatocytes were preserved up to 18 months leading to fulminant hepatic failure in mice. 14 after transplantation into the spleen. 2 However, without im-
In the present study, we showed the importance of the FasL-mediated cytotoxicity in the CD28-independent pathway of allogeneic hepatocyte rejection.