A. L. W. F. Eddleston

ENHANCED TUMOUR NECROSIS FACTOR AND INTERLEUKIN-1 IN FULMINANT HEPATIC FAILURE

Sepsis and endotoxaemia are common in fulminant hepatic failure (FHF) and may contribute to multisystem disease in such patients. Tumour necrosis factor (TNF) is a probable mediator of endotoxic shock and infusion of this monokine into animals causes multi-organ failure that shares features with FHF. In patients with FHF, TNF production was increased and correlated closely with activity of interleukin-1, another cytokine that is released by monocytes/macrophages in response to infection and endotoxin and is produced in increased quantities in FHF. Interleukin-2 activity was impaired in FHF and correlated negatively with TNF production.

INADEQUATE ANTIBODY RESPONSE TO HBAg OR SUPPRESSOR T-CELL DEFECT IN DEVELOPMENT OF ACTIVE CHRONIC HEPATITIS

Abstract The progressive liver damage of active chronic hepatitis is due, it is postulated, to an autoimmune reaction directed against an hepatocyte surface lipoprotein which is initiated in most cases by a hepatitis-B-virus infection. T cells recognising viral determinants activate B cells responsive to the lipoprotein antigen, and where virus infection persists because of a defect in the antibody response to HBAg the autoimmune response is continuously activated. In contrast, in the HBAg-negative group the virus is eliminated normally and the autoimmune reaction persists because of a defect in the suppressor effect of T cells on B cell activity. A genetic marker of this defect may be the histocompatibility antigen HL-A8 which is found in an increased frequency only in the HBAg-negative cases. Correcting the basic defects by specific immunotherapy is a possibility for the future.

Detection of Antibodies Directed against a Liver-Specific Membrane Lipoprotein in Patients with Acute and Chronic Active Hepatitis

A specific and sensitive radioimmunoassay was used to measure the levels of antibody to a liver-specific membrane lipoprotein in patients with acute and chronic liver disease. Antibody was detected in 29 of 30 patients with chronic active hepatitis (all of 15 HBsAg-negative and 14 of 15 HBsAg-positive cases), and in 10 of 17 patients with chronic persistent hepatitis but at significantly lower titer. The titer of antibody to the lipoprotein showed a significant correlation with activity of disease as judged histologically and biochemically. Transiently elevated levels were found in 20 of 21 patients with acute viral hepatitis, but there was no correlation with the degree of liver damage. Antibody to liver-specific membrane protein may be part of the final common pathway of liver-cell damage in both HBsAg-positive and HBsAg-negative chronic activite hepatitis, whereas other immune mechanisms determine the liver-cell injury in acute viral hepatitis.

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.

CELL-MEDIATED IMMUNITY TO A HUMAN LIVER-SPECIFIC ANTIGEN IN PATIENTS WITH ACTIVE CHRONIC HEPATITIS AND PRIMARY BILIARY CIRRHOSIS

Abstract An organ-specific lipoprotein has been isolated from normal human liver and cell-mediated immune responses to it have been assayed in patients with chronic liver diseases using the leucocyte-migration test. Significant inhibition of migration was almost completely restricted to those patients with postulated autoimmune diseases of the liver, being found in 69% of patients with active chronic hepatitis and in 50% of those with primary biliary cirrhosis. The patients with active chronic hepatitis and normal migration indices had shown a satisfactory response to immunosuppressive therapy, with normal liver-function tests at the time of assay.

Spontaneous production of tumour necrosis factor α and interleukin-1β during interferon-α treatment of chronic HBV infection

Abstract Seven chronic carriers of hepatitis B virus (HBV) were studied during treatment with interferon-α to determine whether tumour necrosis factor α (TNFα) or interleukin-1β (IL-1β) contributed to the elimination of HBV. Four patients responded to interferon-α with clearance of HBeAg and permanent inhibition of HBV replication within 3-12 weeks; in each of these patients, the changes were accompanied by substantial rises in spontaneous in-vitro production of TNFα and IL-1β by peripheral blood mononuclear cells from previously undetectable levels. There was little or no change in spontaneous TNFα and IL-1β production in the three patients who did not lose HBeAg in response to interferon-α. These findings suggest that TNFα and IL-1β may contribute to the permanent elimination during interferon-α treatment of hepatocytes supporting viral infection and that the therapeutic potential of these cytokines is worthy of investigation.

ANTIGEN SPECIFIC SUPPRESSOR CELL FUNCTION IN AUTOIMMUNE CHRONIC ACTIVE HEPATITIS

An indirect migration inhibition assay has been used to show that lymphocytes from 26 of 29 patients with autoimmune chronic active hepatitis (CAH) generated T lymphocyte migration inhibitory factors (T-LIF) in the presence of liver specific protein (LSP), compared with only 1 of 21 patients with HBsAg-positive chronic liver disease and none of 19 controls. Generation of T-LIF activity in response to LSP was not observed in any of 5 patients with autoimmune thyroid disease although their T lymphocytes did generate T-LIF activity in the presence of thyroid membrane antigens. T lymphocytes from 1 patient with autoimmune liver and thyroid disease generated T-LIF activity in the presence of both LSP and thyroid membrane antigens. The generation of T-LIF activity by T cells from autoimmune CAH patients was suppressed when these cells were co-cultured in a 9:1 ratio with T cells from normal subjects and patients with HBsAg-positive chronic liver disease, but was unaffected if co-cultured with T cells from other patients with autoimmune CAH. T cells from patients with autoimmune CAH did, however, suppress the generation of T-LIF activity by T lymphocytes from patients with autoimmune thyroid disease when these cells were cultured with thyroid membrane antigens. After pretreatment with cimetidine or mitomycin-C for 30 min, T cells from normal subjects lost their ability to inhibit the generation of T-LIF activity to T lymphocytes from autoimmune CAH patients. These results are consistent with the hypothesis that there exists a defect in the specific suppressor T cell population controlling the immune response to LSP in autoimmune CAH which is unaffected by disease activity and treatment and which may be of fundamental importance in the pathogenesis of the disease.

VIRAL INFECTION AND CANCER

Infection with specific viruses has a role in the pathogenesis of some cancers in human beings. However, the incidence of such cancers is much lower than the frequency of virus infection, suggesting either that infection alone does not result in cancer and that cellular events in addition to the presence of the virus must occur, or that cancer occurs only if viral proteins are expressed in an appropriate cell type or in an immunocompromised host. Molecular analysis of viruses found in association with cancer has revealed that they function, at least in part, by encoding proteins which can associate with and subvert the function of host cell-encoded tumour suppressor proteins which regulate pathways of growth arrest and apoptosis. Better understanding of the mechanisms underlying this association will have diagnostic, prognostic, and therapeutic implications in the near future.

Clinical and prognostic differences in fulminant hepatitis type A, B and non-A non-B.

In 73 patients with fulminant viral hepatitis, non-A non-B hepatitis (NANB) was most common (43.8%), with hepatitis type A (HAV) diagnosed in 31.5% and hepatitis type B (HBV) in 24.7%. The non-A non-B group had a significantly longer duration from the onset of symptoms to the appearance of encephalopathy (median 21 days) compared with the HAV and HBV groups (medians 10 and seven days, p less than 0.01 and p less than 0.005 respectively). In the HAV group the severity of liver damage, judged by the maximum prolongation of the prothrombin time, was significantly less than in the HBV group (58 and 150 seconds prolonged respectively, p less than 0.005), and cerebral oedema was significantly less frequent (39% and 72% respectively, p less than 0.05). Consistent with this, the survival rate was higher in the HAV group (43.4%) compared with the HBV group (16.6%) and NANB group (9.3%) (p less than 0.005). These variations in presentation and clinical course may be a consequence of differences in the pathogenesis of the hepatic necrosis.

Histocompatibility Antigens in Active Chronic Hepatitis and Primary Biliary Cirrhosis

The frequency of antigens HL-A 1 (48%) and HL-A 8 (52%) in 54 patients with active chronic hepatitis from south-east England was significantly higher than in 89 control subjects from the same region (22% and 17% respectively). No correlation could be detected with the age and sex of the patients or with the presence of a particular immunological abnormality but the frequency of HL-A 1 and HL-A 8 was much lower in the nine patients who were positive for HBAg than in the 45 HBAg-negative cases. These results provide further evidence of the importance of genetic factors in active chronic hepatitis. In contrast the frequency of HL-A 1 and HL-A 8 in primary biliary cirrhosis, both in 45 patients from south-east England and in 28 patients from western Scotland, was not significantly different from that found in control groups from the same regions.