T-cell-mediated autologous hepatocytotoxicity in patients with chronic hepatitis C virus infection

Abstract

Virus-specific cytotoxic T lymphocytes (CTLs) have been suggested to be responsible for the liver injuries in patients with hepatitis C virus (HCV) infection. However, there has been no report of direct evidence to substantiate this hypothesis. In this study, we performed in vitro autologous hepatocytotoxicity assay in 45 patients to examine a possible role of CTLs to HCV-infected live cells. The data were correlated with histology activity index of liver biopsy specimens. Lymphocyte subsets and hepatocyte expression of human major histocompatibility complex antigens class I and class II (HLA-I and HLA-II) were also evaluated. The immunohistochemical study showed more prominent HLA-I expression than HLA-II on hepatocytes (mean score +/- SEM:2.34 +/- 0.11 vs. 0.42 +/- 0.08; P < .01). The lymphocyte subset analysis showed that CD8+ T cells were dominant in the lobular areas showing spotty necrosis, whereas CD4+ T cells were prominent in the portal and periportal areas (P < .01). Most patients had a significant T cell-mediated cytotoxicity to hepatocytes as compared with non-T cells (percentage cytotoxicity +/- SEM:46.4 +/- 2.3 vs. 13.8 +/- 2.7; P < .001). T cell-mediated hepatocytotoxicity had a linear correlation with HAI (P < .05). The T cell-mediated cytotoxicity could be blocked by anti-CD8 (43.7% vs. 18.5%, P < .05) but not by anti-CD4 or anti-HLA-II monoclonal antibodies. These findings strongly suggest that HLA-I-restricted, CD8+ T cell-mediated hepatocytotoxicity is an important pathogenetic mechanism in patients with chronic HCV infection.

Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C†

“…Some reports have indicated that cell-mediated host immunity is likely responsible for hepatic inflammation. 37 Inflammatory cells and hepatocytes will induce activation of hepatic stellate cells to initiate fibrogenesis. Emerging evidence suggests that patients with HCV-related mixed cryoglobulin display a particular immune response to HCV infection.…”

Liver‐Associated Natural Killer Activity in Cirrhotic Rats

“…In addition, a decrease in the hepatic NK activity of LGLs obtained from non-cancer liver tissues surrounding human hepatocellular carcinoma, and an increase in its activity from non-cancer liver tissues surrounding metastatic liver cancer were shown (14). Furthermore, it has been reported that hepatic NK cells play an important role in the cytotoxicity to autologous hepatocytes in the same manner as cytotoxic T lymphocytes in patients with chronic hepatitis (23,30).…”

Adaptive T-Cell Response in Pathogenesis of Hepatitis C Infection

“…Имму-носупрессивная терапия сопровождается норма-лизацией повышенного уровня трансаминаз, а ее отмена -усилением активности ВГС [21]. Нали-чие гепатита при ВГС-инфекции ассоциировано с инфильтрацией печени эффекторными иммун-ными клетками [34]. Миграция Т-клеток в печень индуцируется хемокинами (CXCL10, CXCL9 и CCL5), которые продуцируются инфицированными гепатоци-тами и взаимодействуют с рецепторами CCR5 и CXCR3 на поверхности Т-клеток [2,30].…”

“…У пациентов с ХГС в печени обнаружены IL10-продуцирующие CD8 + T-клетки, которые могут оказывать негативное влияние на антиген-специфические CD8 + T-клетки [34]. Кроме того, одним из главных источников IL-10 и TGF-β яв-ляются регуляторные CD4 + Т-клетки (Treg), спо-собные подавлять пролиферацию Т-клеток и их цитокин-продуцирующую функцию либо непо-средственно, либо через иммуносупрессивные цитокины [59].…”