Thursday, September 8, 2011

Cell Mediated Immune Response to HCV

nullSince there is a weak humoral immune response to HCV, it is believed that the reactivity of cytotoxic T-lymphocytes (CTLs) or CD8+ T cells is fundamental to viral elimination (Missale et al., 1996 and Gruner et al., 2000), and that impairment of this reactivity is one of the factors responsible for the chronicity of the infection (Chisari, 1997; Thimme et al., 2001 and Pawlotsky, 2004). The CD8+ T cells can eliminate HCV from the liver through two mechanisms: inducement of apoptosis in infected hepatocytes; and suppression of replication by the production of IFN-γ (Kanto and Hayashi, 2006 and Herzer et al., 2007). The CTL response is less vigorous in chronically infected patients than in those presenting acute infection (Cerny and Chisari, 1999). This can be the result of immunologic tolerance or exhaustion of the CD8+ T cell response to the high viral load that persists in individuals chronically infected with HCV (Cerny and Chisari, 1999).
In addition to CD8+ T cells, CD4+ T cells seem to be involved in the viral damage mediated by the increased expression of MHC class II molecules. Some studies have attributed the vigorous and long-lasting response of CD4+ T cells to the elimination of HCV in the acute form the infection (Cerny and Chisari, 1999 and Wertheimer et al., 2003). However, the loss of the specific CD4+ T cell reactivity to HCV has been associated with the persistence of the virus and the progression of liver damage (Carucci et al., 1997 and Gerlach et al., 1999).
In acute HCV infection, the peak in serum levels of transaminases corresponds with the cell response, which suggests that the hepatic lesion is immune-mediated (Thimme et al., 2001 and Dustin and Rice, 2007). It is known that, after activation, T cells initiate clonal proliferation by secreting cytokines and other substances that can affect hepatic function in a variety of ways (Kerr et al., 1979).
Various cytokines act as mediators in the inflammation caused by chronic hepatitis C and have been related to hepatocyte death, i.e. cholestasis and fibrosis, and paradoxically play a role in regeneration following hepatic injury (Kerr et al., 1979 and Marcellin et al., 2002). It is argued that the imbalance between the production of Th1 and Th2 cytokines is related to the progression of chronic hepatitis C. The expression of Th1 cytokines such as IL-2 and TNF-α has been shown to be related to the more aggressive presentation of hepatic disease, whereas the expression of Th2 cytokines such as IL-10 has been shown to be related to the milder presentation (Napoli et al., 1996).
The production of TNF-α is one of the earliest events in hepatic injury and is the ‘trigger’ for the production of other cytokines (Tilg et al., 2006), as well as being implicated in the inducement of hepatocyte apoptosis in viral hepatitis (Ding and Yin, 2004). The levels of cytokines such as IFN-γ, TNF-α, IL-6 and IL-8 are elevated in individuals with chronic hepatitis C (Tilg et al., 1992; Cacciarelli et al., 1996; Malaguarnera et al., 1997; Oyanagi et al., 1999; Biro et al., 2000; Lapinski, 2001; Polyak et al., 2001; Kamal et al., 2004 and Kasprzak et al., 2004) and some authors have shown that this increase is proportional to the extent of the damage, histologically (Miller and Purcell, 1990; Malaguarnera et al., 1997; Shimoda et al., 1998 and Neuman et al., 2002).
There is evidence that IL-4 can modulate the immune response in HCV-infected individuals (Malaguarnera et al., 1997), principally through the activity of Th2 cells.
It has been shown that IL-10 can suppress proliferation in the Th1 and Th2 responses, as well as inducing anergy (Taylor et al., 2006). There is evidence that IL-10 levels increase in chronic hepatitis C (Cacciarelli et al., 1996). Some studies report reduced inflammatory activity (Nelson et al., 2003), and others report that administration of IL-10 to such patients causes fibrosis (Nelson et al., 2000).
Various studies have shown that TGF-β is increased in chronic hepatitis C and is involved in the progression of fibrosis, which has been challenged by other authors (Roulot et al., 1995 and Nelson et al., 1997). It has been suggested that TGF-β and IL-10 act as immunosuppressive agents in the liver (Knolle and Gerken, 2000). In addition, both have been shown to inhibit the immune response and regulate the activity of dendritic cells (Racanelli and Rehermann, 2006), which can establish a balance between the Th1 and Th2 responses in chronic diseases (Yazdanbakhsh et al., 2002).

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