Lymphocyte cytotoxicity in chronic active hepatitis: effect of therapy and correlations with clinical and histological changes.

A study of lymphocyte cytotoxicity for rabbit hepatocyte cultures in 15 patients with untreated chronic active hepatitis showed positive results in all cases, both HBsAg positive and negative. After immunosuppressive therapy cytotoxicity became negative and remained negative, in four of nine patients followed serially. In 51 patients established on therapy for periods from three months to 12 years, cytotoxicity was negative in 19 and all patients are currently alive. However, in the remaining 32 patients in whom cytotoxicity was positive there has been a 34% mortality. Cytotoxicity remained persistently positive in 12 of 15 patients followed serially, and persistently negative in seven of nine. Cytotoxicity showed a significant association with histological disease activity, especially the extent of piecemeal necrosis, but not with biochemical tests of liver function, immunoglobulins, or autoantibodies. The basis of this cytotoxicity test is an antibody dependent cell-mediated autoimmune reaction directed against a liver specific protein, and the results suggest that in some cases immunosuppressive therapy is followed by control of this reaction. It may be possible to stop therapy in these patients, but in those in whom the reaction continues, as shown by continuing cytotoxicity, the prognosis is not as good and the use of other drug schedules would seem worthy of trial.

Lymphocyte cytotoxicity for isolated hepatocytes in alcoholic liver disease.

To determine whether an autoimmune reaction to liver-specific proteins occurs in alcoholic liver disease, the cytotoxic effect of lymphocytes on isolated hepatocytes was determined in 27 alcoholic patients. Cytotoxicity was demonstrated in 15 of 17 patients with a histological diagnosis of alcoholic hepatitis, but in none of 10 with other forms of alcoholic liver disease. The ability of a liver-specific membrane lipoprotein to block the reaction suggests that sensitization to this antigen is responsible for the cytotoxicity. The demonstration of cytotoxicity using T cell-depleted, but not B and K cell-depleted, lymphocytes suggests an antibody-dependent cell-mediated reaction. There was a close correlation between cytotoxicity and the presence of alcoholic hyalin, liver cell necrosis, and piecemeal necrosis, but not with other histological features, immunoglobulines, autoantibodies, or standard liver function tests. The persistence of this autoimmune response, induced in some way by alcohol or one of its metabolites, may be important in the progression of acute alcoholic hepatitis to chronic liver disease.

Autoimmune reaction to a liver specific membrane antigen during acute viral hepatitis.

Lymphocyte cytotoxicity for isolated hepatocytes has been demonstrated in 93% of cases of acute viral hepatitis tested within two weeks of the onset of symptoms. The frequency of cytotoxicity during this time was similar for HBsAg positive and negative cases. However, after this time it was significantly higher in HBsAg positive than negative cases, 90% and 25% respectively (P less than 0-01). Cytotoxicity was found in B-cell, but not T-cell, enriched fractions of lymphocytes, compatible with an antibody-dependent K-cell mediated reaction. In two cases the assay remained positive on retesting six months later, and follow-up liver biopsies showed the features of chronic aggressive hepatitis. These findings suggest that, in addition to the known immunological reactions against viral antigens that occur during the acute phase of viral hepatitis, an autoimmune reaction directed against a liver specific protein is also initiated; and if this reaction persists then chronic hepatitis may develop.

Lymphocyte cytotoxicity for kidney cells in renal tubular acidosis of autoimmune liver disease.

Sensitisation to a renal tubular antigen, Tamm-Horsfall glycoprotein, has been shown to be common in patients with renal tubular acidosis complicating autoimmune liver disease, and it has been suggested that this immune reaction, by damaging renal tubular cells, might be responsible for the acidification defect. The lymphocytes from 10 out of 13 patients with chronic active hepatitis or primary biliary cirrhosis and an associated renal tubular acidosis were shown to be cytotoxic for a kidney cell line known to secrete Tamm-Horsfall glycoprotein. The cytotoxic reaction was blocked by this antigen, but not by two other proteins, indicating that sensitisation to the renal glycoprotein was the likely cause of the target cell damage. Significant reduction in cytotoxicity after the addition of aggregated IgG suggested that the reaction was of the antibody-dependent cell-mediated type. These results, together with the finding of antigenic material in the surface membrane of liver cells that cross reacts immunologically with Tamm-Horsfall glycoprotein, provide an explanation for the association between chronic liver disease and renal tubular dysfunction.

Antibody-dependent cell-mediated (K cell) cytotoxicity against isolated hepatocytes in chronic active hepatitis.

Lymphocytes from 12 of 17 patients with chronic active hepatitis were cytotoxic towards isolated hepatocytes in a microcytotoxicity assay. Enriched fractions of B cells, prepared by removal of E-rosetted cells, were cytotoxic in all 12 cases, whereas T-cell fractions, prepared by removal of erythrocyte-antibody-complement-rosetted cells, were cytotoxic in only 1 case (P less than 0-0005). HBsAg positive and negative cases reacted similarly. In 6 patients the addition of 5 mug aggregated IgG significantly reduced cytotoxicity from 54% +/- 15 to 13% +/- 15 (mean +/- 1S.D.) suggesting that K cells may be the effector cell in an antibody-dependent, cell-mediated reaction directed against a liver-specific membrane lipoprotein.