Nonisotopic in situ hybridization using a digoxigenin-labeled cDNA probe to the 3' nonstructural region (NS5) of hepatitis C virus (HCV) was performed on liver tissue from 33 patients. The results were compared with PCR detection of HCV RNA performed on 24 of the biopsies. Nonisotopic in situ hybridization correlated well with PCR findings. Hybridization signals were detected, within the cytoplasm and nuclei/ nucleoli of hepatocytes, mononuclear, and biliary epithelial cells. In patients with clinically and histologically defined chronic active hepatitis related to active HCV infection, HCV genome was frequently detected in biliary epithelium and correlated well with biliary damage, an otherwise uncommon finding in chronic active hepatitis due to other hepatotropic viruses. Further studies using sense and antisense probes synthesized from the 5' noncoding region of the HCV genome confirmed the localization of positive strand of HCV in the above cell populations. The replicative intermediate strand was also present in all cells, although less frequently observed, apart from biliary epithelium, where negative strand of HCV was undetectable. The findings of HCV genome in liver biopsies of two patients with no significant histological abnormalities may suggest that the damage seen in chronic HCV infection is immune mediated, although the cytopathic effect of the virus may also be important. (J.
SUMMARY A randomised controlled trial of thymic hormone extracts (Thymostimulin) (1 mg/kg/day for seven days; 1 mg/kg/weekly thereafter) was undertaken in 30 patients (21 women, nine men) with treated, apparently inactive 'autoimmune' chronic active hepatitis during withdrawal of maintenance corticosteroid and azathioprine therapy. Reactivation of disease occurred in 26 patients (86%) during or after treatment withdrawal and was as frequent in the Thymostimulin treated (11 of 13; 84%) and untreated (15 of 17; 88%; p>OO5) groups. Reactivation of disease was accompanied by a severe defect in concanavalin A induced suppressor cell activity, the magnitude of which was similar in the Thymostimulin treated and untreated groups (mean % suppression = 16*4 and 3-2 respectively; p>O0O5 vs 84*4 in control subjects). Further studies assessing the optimal dose, duration of treatment, and mode of administration are required to establish a therapeutic role for thymic hormone extracts in 'autoimmune' chronic active hepatitis.
SUMMARYReduced suppressor cell number and function have been described in a number of autoimmune diseases and this may contribute to pathogenesis. Suppressor cell function depends upon the interaction of the CD8 antigen expressed on suppressor cells with other limbs of the immune system. Recently, soluble membrane antigens including CD8 have been identified in serum and it is possible that the loss of such antigens from viable cells could result in functional deficit. In order to examine whether the decreased suppressor cell function reported in autoimmune type of chronic liver disease is associated with soluble serum CD8 levels, sera from 23 patients with primary biliary cirrhosis (PBC), 12 with autoimmune chronic active hepatitis (AI-CAH) and 21 healthy controls were tested using a commercially available enzyme immunoassay. The proportion of cells expressing the CD8 antigen and the intensity of its display were also determined using an immunofluorescent technique and an ELISA, respectively, for 12 PBC and 10 healthy controls. The soluble serum CD8 levels were significantly higher in PBC (mean U/ml + s.d., 777 + 331), and AI-CAH (575 + 291) than controls (322 + 115) (P < 0-001 and P= 0 004, respectively). While the intensity of CD8 antigen expression on suppressor/cytotoxic populations was not significantly different in PBC (347 + 125 per 104 cells) compared with controls (441 + 206), the mean proportion of CD8 positive cells was significantly less in PBC (141 +68%) than controls (20+4 7%) (P<0 05). These data suggest that the apparent reduction in suppressor cell number found for patients with PBC and AI-CAH may be a consequence of the shedding or secretion of CD8 antigen from cell membrane of CD8 positive lymphocyte. It is also possible that the loss of this antigen is responsible for the reduced suppressor cell function seen in these conditions.
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