Tumor necrosis factor alpha (TNF-alpha) is a cytokine with pleiotropic properties that is induced in a variety of pathological situations including viral infections. In this work, we analyzed the expression of TNF-alpha gene in patients with chronic hepatitis C. Serum TNF-alpha levels were found to be elevated in all chronic hepatitis C patients including those cases presenting sustained biochemical remission of the disease after interferon therapy. Untreated patients with chronic hepatitis C showed increased TNF-alpha messenger RNA (mRNA) levels in the liver and mononuclear cells as compared with healthy controls. After completion of treatment with interferon, patients experiencing sustained complete response showed values of TNF-alpha mRNA, both in the liver and in peripheral mononuclear cells, within the normal range, significantly lower than patients who did not respond to interferon and than those with complete response who relapsed after interferon withdrawal. Pretreatment values of TNF-alpha mRNA were lower in long-term responders to interferon than in cases who failed to respond to the treatment. Values of TNF-alpha mRNA in the liver or in mononuclear cells were higher in specimens with positive hepatitis C virus (HCV) RNA than in those samples where the virus was undetectable. Neither the intensity of the liver damage nor the amount of HCV RNA in serum or in cells showed correlation with the levels of TNF-alpha transcripts in peripheral mononuclear cells but it was found that high TNF-alpha values were associated with genotype 1b. In conclusion, there is an enhanced expression of TNF-alpha in HCV infection. High levels of this cytokine may play a role in the resistance to interferon therapy.
Patients infected with hepatitis C virus (HCV) have an impaired response against HCV antigens while keeping immune competence for other antigens. We hypothesized that expression of HCV proteins in infected dendritic cells (DC) might impair their antigen-presenting function, leading to a defective anti-HCV T-cell immunity. To test this hypothesis, DC from normal donors were transduced with an adenovirus coding for HCV core and E1 proteins and these cells (DC-CE1) were used to stimulate T lymphocytes. DC-CE1 were poor stimulators of allogeneic reactions and of autologous primary and secondary proliferative responses. Autologous T cells stimulated with DC-CE1 exhibited a pattern of incomplete activation characterized by enhanced CD25 expression but reduced interleukin 2 production. The same pattern of incomplete lymphocyte activation was observed in CD4 ؉ T cells responding to HCV core in patients with chronic HCV infection. However, CD4؉ response to HCV core was normal in patients who cleared HCV after alpha interferon therapy. Moreover, a normal CD4 ؉ response to tetanus toxoid was found in both chronic HCV carriers and patients who had eliminated the infection. Our results suggest that expression of HCV structural antigens in infected DC disturbs their antigen-presenting function, leading to incomplete activation of anti-HCV-specific T cells and chronicity of infection. However, presentation of unrelated antigens by noninfected DC would allow normal T-cell immunity to other pathogens.Hepatitis C virus (HCV) is a single-stranded RNA virus belonging to the Flaviviridae family (25). Although some patients exhibit acute self-limited infection, a characteristic feature of HCV is the high incidence of persistent infection and chronic hepatitis, with a strong risk for the development of hepatocellular carcinoma (10). This high incidence of chronicity suggests that the virus has developed efficient mechanisms to escape host immune responses. Indeed, although most patients have anti-HCV antibodies (38), cellular immune responses are weak in chronically infected patients. It has been reported that CD4 ϩ T-cell responses against viral antigens are vigorous in individuals who have cleared HCV after acute infection or after treatment with alpha interferon (IFN-␣) (11,21,26,35). By contrast, patients who fail to respond to therapy exhibit poor T-cell reactivity against viral proteins. Regarding CD8 ϩ lymphocytes, low responses have been detected in infected patients (7,32,37), and recent reports show that these cells play a critical role during the acute phase of the disease (8). Thus, chronicity of HCV infection is related to the inability of HCV-specific CD4 ϩ and CD8 ϩ T cells to accomplish efficient effector functions. These defects, however, are not the result of general immunosuppression since T-cell immunity to other pathogens is well preserved in patients with chronic HCV infection.HCV may evade immune surveillance by different mechanisms including mutations in regions that are targets for the immune system (13,40,41)...
To investigate the involvement of T-cell response against hepatitis C virus (HCV) antigens in viral clearance after interferon therapy, we measured interleukin-2 (IL-2) production by peripheral mononuclear cells in response to HCV core in patients with chronic hepatitis C. In a cohort of 43 patients, we investigated the frequency of circulating corespecific T-helper (Th) cell precursors by the limitingdilution assay, and in a second cohort of 60 patients, we analyzed the response to specific core epitopes using 52 synthetic 15-mer overlapping peptides. We observed that the frequency of core-specific Th cell precursors was significantly higher in patients with sustained biochemical and virological response (SR) after interferon (
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