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T lymphocytes and immunoregulatory cytokines may be important in the host response to hepatitis C virus (HCV) infection. T-helper type 1 (Th1) cytokines (interleukin [IL]-2, interferon gamma [IFN-gamma]) are required for host antiviral immune responses, including cytotoxic T-cell generation and natural killer cell activation, while T-helper type 2 (Th2) cytokines (IL-4,IL-10) can inhibit the development of these effector mechanisms. In this study, the serum levels of Th1 and Th2 cytokines in patients (n = 23) infected with HCV were measured and compared with biochemical (alanine transaminase [ALT]) and viral (HCV RNA) indicators of infection. Serial cytokine levels were measured in a subset of 11 patients at 1 and 12 weeks during and at 1 week after interferon alfa (IFN-alpha) therapy (n = 33 samples). Levels of circulating IL-2, IL-4, IL-10, and IFN-gamma were significantly elevated in HCV patients versus normal controls (128 vs. 25 pg/mL, 3,045 vs. 29 pg/mL, 2,949 vs. 18 pg/mL, and 307 vs. 24 pg/mL respectively; P < .01). Treatment with IFN-alpha decreased the levels of IL-4 (321 +/- 224 pg/mL), and IL-10 (1,011 +/- 344 pg/mL), which paralleled a decrease in HCV RNA (114 +/- 27 vs. 25 +/- 20 Eq/ml X 10(5), pre- vs. post-IFN-alpha [12 weeks];P <.05). These findings indicate that an activated T-cell response, as manifest by increased circulating immunoregulatory cytokines, is present in patients with HCV liver disease. Furthermore, treatment with HCV liver disease. Furthermore, treatment with IFN-alpha diminishes the Th2 cytokine response. Thus, modulation of T-cell function and cytokine production may be one mechanism whereby IFN-alpha therapy results in reduced viral burden.

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver with unknown etiology. Autoreactive T lymphocytes that infiltrate the liver may play a major role in the bile duct damage that accompanies the disease. We hypothesized that cytokines produced by T lymphocytes and other cells are central to the disease process. Therefore, we used reverse transcription-polymerase chain reaction (PCR) and Southern hybridization to identify cytokine message directly from liver tissue of 11 patients with PBC and 5 patients with autoimmune hepatitis (AI-CAH). Messenger RNA (mRNA) for interleukin (IL)-2, IL-5, IL-6, interferon gamma (IFN-gamma), and transforming growth factor beta (TGF-beta) were detected in the majority of the specimens from patients with PBC. The presence of IL-5 was associated with PBC (P < .001, PBC vs. AI-CAH). Because IL-5 is a potent eosinophil differentiation factor, we looked for evidence of activated eosinophils within the infiltrate. We observed the deposition of the primary cytotoxic granule protein of eosinophils, major basic protein (MBP), within the portal region of livers from patients with PBC. Moreover, we detected message for a cytotoxic T-lymphocyte (CTL) granzyme in 87.5% of these livers indicating that mature CTL are present. Thus, we present evidence for two effector pathways that may contribute to the tissue damage observed in PBC and have identified message for cytokines that may regulate these pathways.

These data raise the possibility that soluble Fas, produced by hepatocytes, may influence the immune response by blocking Fas-mediated apoptosis and, thus, may have a role in liver transplantation.

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