Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) have been shown to play a role in host defense and pathogenesis of chronic HCV infection. Our aim was to test the hypothesis that intrahepatic HCV-specific CTL activity may impact subsequent response to interferon alfa (IFN-␣) therapy. Of the 37 patients that we have prospectively evaluated for HCV-specific CTL activity in liver, 21 received IFN therapy, and 19 completed a 6-month course and attended 6 to 18 months of follow-up. Intrahepatic CD8 ؉ cells were isolated from liver biopsy tissue and tested against target cells expressing HCV antigens to determine intrahepatic CTL activity. The relationship between treatment response and HCV-specific CTL activity and other factors known to associate with response (genotype, viremia, histology) was analyzed. HCV-specific CTL activity was detected in 9 of 21 patients (and 9 of 19 who completed therapy). After 6 months of IFN therapy, 8 of 19 (42%) patients had normal serum alanine transaminase (ALT) (complete responders). After 18 months of follow-up, only 3 patients (16%) had a sustained biochemical response. Of the 9 patients with detectable HCV-specific CTL activity in their liver before treatment, 7 (78%) developed a complete response. In contrast, only 1 of the 10 patients with no detectable HCV-specific CTL activity developed a complete response to IFN (P F .01). In 6 of 8 patients with a complete response, including the 3 sustained responders, the CTL response appeared to be directed predominately to the HCV core region. These data suggest that the host immune response, particularly that mediated by CD8 ؉ CTL, may be important in determining the outcome of IFN therapy for chronic HCV infection. Further understanding of the mechanism of action of IFN should impact the design of better therapeutic strategies against chronic HCV infection. (HEPATOLOGY 1998;28:225-230.)The host cellular immune defense, including the CD4 ϩ and CD8 ϩ T-cell response, is activated in patients with hepatitis C virus (HCV) infection. The intensity of the T-cell response during the early stages of infection may be a critical determinant of disease resolution and control of infection. 1,2 In chronic viral infection, viral-specific CD8 ϩ cytotoxic T lymphocytes (CTL) have been shown to be important in host defense and in the control of the viral infection. [3][4][5][6][7] In lymphocytic choriomeningitis virus infection, virus-specific CTL activity reduces viral titers by 4 to 5 logs. 8 It is felt that CTL might lead to viral clearance through either direct lysis of infected cells or cytokine-mediated mechanisms. We and others have shown that HCV-specific CTL activity is detectable in the liver in a proportion of patients with chronic HCV infection. The presence of HCV-specific CTL activity in bulk-expanded CTL was found to be associated with a lower level of viremia and a greater inflammatory activity in the liver, suggesting that HCV-specific CTLs may assist in the control HCV infection, but, in so doing, contribute to hepatoce...
We read with great interest the recent article by Kugelmas et al., 1 reporting plasma cytokine levels in patients with NASH and the effect of diet and vitamin E on this disease. They found that plasma tumor necrosis factor (TNF), interleukin 8, and interleukin 6 concentrations were significantly elevated compared with control values, and only plasma interleukin 6 levels significantly decreased with diet therapy. This article further reported that vitamin E therapy did not independently influence the biochemical data and plasma cytokine levels in patients with NASH. We previously investigated the plasma transforming growth factor-1 (TGF-1) level and the efficacy of vitamin E in patients with NASH. 2 We enrolled 12 patients with NASH and 10 with fatty liver. All patients were given dietary instruction for 6 months, and thereafter vitamin E (-tocopherol acetate, Juvera™, Eisai Pharmaceutical Co., Tokyo, Japan, 300 mg/day; 100 mg is equivalent to 100 IU) was given for 1 year. In consequence, the plasma TGF-1 level in patients with NASH (37 5 ng/ml) was significantly higher than that in patients with fatty liver (10 4 ng/ml) and healthy subjects (9 5 ng/ml). Moreover, this elevated plasma TGF-1 level decreased after a 1-year vitamin E treatment, together with the improvement of biochemical markers and hepatic pathological findings (Table 1). In 5 out of 9 NSAH patients in whom liver biopsy was performed after vitamin E treatment, inflammation and fibrosis were improved. On the other hand, diet therapy improved biochemical data only in patients with fatty liver, but not in those with NASH. We conducted our previous study to assess the efficacy of a long-term vitamin E treatment (a 1-year vitamin E administration after a 6-month diet). However, in the studies performed by Kugelmas et al., 1 vitamin E was given for only 12 weeks and the patients were given diet therapy at the same time. In fact, Kugelmas et al. 1 mentioned that longer study duration might have shown the efficacy of vitamin E on NASH. However, we had already reported the efficacy of a 12-month treatment of vitamin E on NASH. Moreover, long-term treatment with vitamin E for patients with NASH was tried for obese children and Japanese adults, and the beneficial effect of this vitamin has already been confirmed. 3,4 In addition, the NIH plans to conduct randomized controlled trials of insulin-sensitizing agents and vitamin E therapy for NASH. 5 Although the role of tumor necrosis factor is currently debated in the literature, 6,7 elevated blood level of TGF-has recently been ascertained. 8 The role of TGF-1 in hepatic inflammation and fibrosis has been well documented in both animal and clinical studies. 9,10 Therefore, for better understanding of the cytokine network in NASH, we believe that the investigation of plasma TGF-1 is essential , as well as long-term observation of vitamin E treatment.
Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the host's immunomodulatory response to infective agents. To evaluate the TNF-alpha system in patients with chronic hepatitis C virus (HCV) infection, plasma, serum, and peripheral blood mononuclear cells (PBMC) were prospectively collected from 53 patients and 33 healthy control subjects. Circulating TNF-alpha and TNF receptors were assayed by their respective enzyme immunoassays. In addition, TNF-alpha mRNA was quantitated in PBMC using a branched DNA assay, and production of TNF-alpha by PBMC with and without lipopolysaccharide was also assessed. Patients with chronic HCV infection had a higher level of circulating TNF-alpha compared to healthy control subjects (9.62 +/- 6.01 vs 3.66 +/- 1.23 pg/ml, P < 0.001). They also had higher circulating levels of TNF receptors compared to control (CD120a: 3323 +/- 1267, pg/ml, N = 49 vs 1855 +/- 422 pg/ml, N = 33, P < 0.001; CD120b: 1290 +/- 650 pg/ml, N = 51, vs 863 +/- 207 pg/ml, N = 33, P < 0.001). Plasma TNF-alpha level correlated with circulating CD120a (r = 0.52, N = 49, P < 0.001) and weakly with CD120b (r = 0.32, N = 51, P = 0.02). Plasma TNF-alpha also correlated with markers of hepatocellular injury, including ALT (r = 0.34, N = 53, P = 0.01) and alpha-GST (r = 0.31, N = 43, P = 0.042), but not with serum HCV RNA levels. There was no difference in the TNF-alpha mRNA levels in PBMC between patients with chronic HCV infection (1.4 +/- 1.9 units/10[6] cells, N = 8) and healthy control subjects (2.1 +/- 1.4 units/10[6] cells, N = 8, P = NS). There was also no difference in the spontaneous production of TNF-alpha by PBMC (1 x 10[6] cells/ml) between patients with chronic HCV infection (14.2 +/- 36.5 pg/ml, N = 11) and healthy subjects (11.9 +/- 14.0 pg/ml, N = 14, P = NS). However, patients with chronic HCV infection produced more TNF-alpha upon stimulation with lipopolysaccharide compared to healthy control subjects (1278 +/- 693 pg/ml, N = 11, vs 629 +/- 689 pg/ml, N = 14, P < 0.05). These data indicate that the TNF-alpha system is activated in patients with chronic HCV infection.
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