Search

In a micrototoxicity assay, lymphocytes from ten out of sixteen patients with HBsAg-negative chronic active hepatitis have been shown to be cytotoxic to autologous hepatocytes isolated from percutaneous liver biopsies. This cytoxicity was demonstrable in all six untreated patients but in only four out of ten receiving immunosuppressive treatment, the presence of cytotoxicity showing a significant association with the activity of the disease assessed histologically. The addition of excess purified lipoprotein (LSP), derrived from the hepatocyte plasma membrane, blocked the reaction in all cytotoxic cases, indicating that LSP was the major target antigen. Enriched fractions of T cells were cytotoxic in only one case, whereas non-T cell fractions were cytotoxic in the other ten cases investigated in this way. For optimum T cell cytotoxicity, effector and target cells must share histocompatibility determinants and the results of this study using an autologous system show conclusively that the lymphocyte cytotoxicity found in HBsAg-negative chronic active hepatitis is mediated by a non-T cell population.

To investigate the possible role of cell mediated cytotoxicity in the pathogenesis or perpetuation of liver damage associated with alpha 1-antitrypsin (AAT) deficiency, peripheral blood lymphocytes (PBL) from 13 children with PiZZ phenotype who had had liver disease in infancy were incubated with autologous hepatocytes in a microcytotoxicity assay. There was a clear trend for cytotoxicity to increase with age and thus significantly increased cytotoxicity was found in four cases older than 2 years, while intermediate values were recorded in three children between 6 months and 2 years and normal values in children younger than 6 months. Fractionation of PBL into T and non-T-enriched subsets showed that both were involved in the cytotoxic reaction. A purified liver membrane lipoprotein preparation (LSP) inhibited both T and non-T-cell cytotoxicity suggesting that LSP is a major target antigen in this system. Control experiments performed in infants with neonatal hepatitis syndrome, but with normal Pi phenotype, showed consistently increased cytotoxicity values. Cell-mediated immune reactions directed against autologous hepatocytes develop late in the course of the liver disease associated with AAT deficiency. While this reaction cannot be involved in the pathogenesis of the initial liver lesion, it may contribute to perpetuation of liver damage.

A test of lymphocyte cytotoxicity for isolated adult rabbit hepatocytes has been performed using lymphocytes from 40 children with acute or chronic liver disease. Positive cytotoxicity was not observed in 26 children without liver disease and rarely in 13 children with disease affecting primarily the biliary tract. Temporarily positive tests were found in those with acute hepatocellular disease, but tests remained positive in patients with chronic active hepatitis, while liver function tests remained abnormal. Persistently positive test occurred in those with liver disease associated with alpha-antitrypsin deficiency. Such altered immunoresponsiveness could be an important pathogenic mechanism leading to chronic liver disease in childhood.

Anti-lymphocytic antibodies (ALA) have been described in a variety of autoimmune disorders. We have investigated the presence of ALA in autoimmune chronic active hepatitis (aCAH) starting in childhood. Using a modified Terasaki technique ALA were found in 17 of 18 patients with aCAH but in only one of 15 patients with alpha-1-anti-trypsin deficiency or Wilson's disease and three of 27 aged-matched healthy controls (P < 0.0005 for both). Sera from 12 patients with uncontrolled aCAH had significantly higher cytotoxicity values than sera from six children with inactive disease (P < 0.01). ALA were directed to T but not B lymphocytes and were not reactive with specific HLA antigens. No preferential killing was observed against CD4 or CD8 positive T lymphocytes. Characterization of ALA revealed them to be cold-reactive IgM. The possible role of ALA in aCAH is discussed. [ABSTRACT FROM AUTHOR]

Con A stimulated suppressor cell function and the proportion of suppressor T cells were reduced in children with untreated chronic active hepatitis (CAH) but were normal in corticosteroid treated CAH patients, patients with severe acute hepatitis and inactive chronic liver disease. Adults with CAH also have defective suppressor function hut a normal proportion of T suppressor cells. This difference may account for the observation that relapse after treatment withdrawal is less frequent in children than in adults. [ABSTRACT FROM AUTHOR]