Involvement of the Fas System in Hepatitis C Virus Recurrence After Liver Transplantation

Abstract

To date, there have been no reports of the involvement of the Fas system in recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT). In 25 patients who underwent OLT for HCV-related liver cirrhosis, we evaluated the expression of the Fas antigen (FasAg) on hepatocytes, apoptic hepatocytes, and serum levels of soluble Fas (sFas). The level of HCV viremia and HCV genotype were determined by polymerase chain reaction. Serum sFas levels were determined by an enzyme immunoassay procedure. DNA fragmentation was determined by the terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end-labeling (TUNEL) technique on deparaffinized liver samples. FasAg expression was evaluated by an immunoperoxidase method. Sixteen patients had evidence of recurrent HCV disease. The number of hepatocytes expressing FasAg and the percentage of apoptotic hepatocytes was greater among patients who developed recurrent hepatitis than among those who did not (P < .01 and P < .0001, respectively). There was a correlation between hepatic expression of FasAg, intensity of lobular inflammation (P ‫؍‬ .007), and TUNEL index (P < .001). The levels of sFas were greater among the patients with recurrent HCV hepatitis than those without recurrent hepatitis (P < .04). We conclude that (1) Fas expression is up-regulated in recurrent HCV after OLT and is related to the grading of liver disease; likewise, levels of sFas were greater in the patients with recurrent HCV hepatitis; and (2) the demonstration of hepatocytes with FasAg expression and the labeling of the nuclei by TUNEL assay suggest that hepatic apoptosis mediated by the Fas system may have a role in the pathogenesis of recurrent HCV hepatitis after OLT. (Liver Transpl 2000;6:562-569.) H epatitis C virus (HCV)-related cirrhosis currently accounts for approximately 25% to 40% of the indications for orthotopic liver transplantation (OLT). 1,2 Despite the nearly universal recurrence of HCV viremia, the degree to which recurrent hepatitis is recognized histologically varies markedly. [3][4][5][6] Factors that determine the frequency and severity of the disease have not been clearly identified, but a number of interrelated variables are probable, including level of HCV viremia, HCV genotype, and degree and type of immunosuppression. 2,3-6,7-9 However, the mechanism of liver cell damage in the patients with recurrent HCV liver disease is unknown.The apoptotic process, or programmed cell death, can be induced by stimuli of the so-called death receptors, such as the tumor necrosis factor (TNF) receptor-1, DR-3, DR-4, or Fas (APO-1, CD95). The Fas receptor or Fas antigen (FasAg) is a 45-kd cell-surface type 1 plasma membrane protein expressed in lymphoid and many other tissues. The receptor is activated through oligomerization on binding of its ligand (FasL) to its extracellular domain, and the apoptotic signal is transduced through the so-called death domain. [10][11][12] FasAg is one of the best-identified cell-surface molecules that mediate exter...

Impact of immunosuppression on immunopathogenesis of liver damage in hepatitis C virus-infected recipients following liver transplantation

“…28 Increased activity of this hepatitic disease also is associated with increased liver Fas mRNA levels and increased hepatocyte apoptosis. 29,30 In all studies, these responses occurred at a virological level at least one log greater than in the nontransplantation setting. 31 In one study, there was a correlation between liver Fas mRNA and viremia levels, providing evidence that the cycle of inflammation and apoptosis is greater than in the pretransplantation setting.…”

HBV and HCV Infections and Acute Rejection Differentially Modulate CD95 and CD28 Expression on Peripheral Blood Lymphocytes After Liver Transplantation

“…Therefore it would be of interest to look for parameters capable of discriminating both complications, because immunosuppression used to treat rejection further increases viral load, and it also accelerates and exacerbates recurrence of hepatitis [9]. A diversity of strategies has been implemented trying to differentiate HCV recurrence from cellular AR, such as quantification of viral HCV RNA copies in liver tissue [29], intragraft immune activation gene expression profiling [30], infiltrating leukocyte or hepatocyte apoptosis rates, as well as the expression of apoptosis related molecules CD95 and CD95L [16,19,20], but none of them became a definitive test capable of distinguishing these two entities. In fact, CD95 and CD95L intragraft protein levels have been repeatedly studied, although conclusions have been drawn that any inflammatory process increased expression of these molecules.…”

Mechanisms of HCV reinfection and allograft damage after liver transplantation

“…This differential gene expression is associated with high levels of cellular apoptosis, proliferation and immune activation significantly higher in the post than the pretransplant chronic HCV disease [36,57,58]. This implies that the rapid progression of HCV post liver transplant is due to the same process as in non-immunosuppressed disease but is occurring at a viral set point at least one log higher than in the non-transplant setting.…”