LIVER-INFILTRATING AND CIRCULATING CD4(-CELLS IN CHRONIC HEPATITIS-C - IMMUNODOMINANT EPITOPES, HLA-RESTRICTION AND FUNCTIONAL-SIGNIFICANCE() T)

The aim was to assess the specificity and functional significance of l iver-infiltrating and peripheral blood T cells in chronic hepatitis C. Peripheral blood mononuclear cells hepatitis C virus from 50 of 58 (8 6.2%) patients with chronic hepatitis C virus infection and 6 of 28 (2 1.4%) controls showed a proliferative T cell response to at least one of 16 synthetic peptides covering highly conserved regions of the core , envelope (E1) and non-structural regions (NS4) of hepatitis C virus. However, six immunodominant peptides were exclusively recognized by t he proliferating blood mononuclear cells from 46 patients with chronic hepatitis C virus infection (79.3%). Fine specificity and HLA-restric tion were studied with 15 peptide-specific CD4(+) T cell lines and 23 T cell clones isolated from liver tissue and peripheral blood of 12 pa tients with chronic hepatitis C. It was demonstrated that the peptide- specific response of CD4(+) T cells was restricted to the presence of autologous accessory cells and HLA-DR and -DP molecules. Fight peptide -specific T cell lines and five T cell clones derived from liver tissu e and peripheral blood, released interferon-gamma (200-6600 pg/ml) and tumor necrosis factor-alpha (100-400 pg/ml) and no or little interleu kin-4 (<140 pg/ml) after peptide-specific or mitogeneic stimulation, t hus resembling a Th1-like cytokine profile. Patients with active liver disease showed significantly higher proliferative responses to hepati tis C virus core peptides than asymptomatic hepatitis C virus carriers or complete responders to interferon therapy. In conclusion, class II -restricted CD4(+) T cell responses to some immunodominant epitopes wi thin the hepatitis core region correlated with disease activity in chr onic hepatitis C virus infection. Functionally, liver-infiltrating and peripheral blood T cells released Th1-like cytokines in response to t he specific stimulus, Thus, it can be suggested that CD4(+) T cells ca n mediate the pathogenesis of chronic hepatitis C virus induced liver disease.