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Biomedical subjects

J Neuberger

Publications and source records attributed to J Neuberger.

At least 145 records · Page 8Linked to original sources
PubMed1986

In vitro effects of lymphoblastoid interferon on lymphocyte activation and cell-mediated cytolysis in patients with chronic hepatitis B virus infection.

In addition to a direct anti-viral effect, interferons have important immunological properties including effects on cell-mediated immunity and antibody production as well as cell-mediated cytolysis. In chronic hepatitis B virus infection the host immune system is important for the elimination of replicating virus and in addition to directly inhibiting hepatitis B virus replication, interferons may affect host immune responses. We investigated the effect of lymphoblastoid interferon in vitro on lymphocyte activation and cell-mediated cytolysis in patients with chronic hepatitis B virus infection. The proliferative response to the mitogen PHA was significantly impaired in patients compared to controls. In addition supernatants of cultured mononuclear cells from patients stimulated with PHA contained less interleukin-2 activity than controls while the proportion of stimulated mononuclear cells expressing the interleukin-2 receptor was also reduced in patients. Prior incubation with 10(3) U ml-1 lymphoblastoid interferon increased both interleukin-2 activity and interleukin-2 receptor expression in patients and controls, although in patients the response was less marked. In contrast the proliferative response was unaffected. Natural killer cell activity against K562 cells was similar in patients and controls which in both groups was significantly augmented by prior incubation with 10(3) U ml-1 lymphoblastoid interferon; the increase was inversely proportional to baseline activity. In contrast incubation of target or effector cells with interferon did not augment T-cell cytotoxicity against autologous hepatocytes. The effects of lymphoblastoid interferon in vitro, were modest, but subtle changes in immunological status in addition to a direct effect on viral replication may be relevant to eventual clearance of the hepatitis B virus.

Cytotoxicity, Immunologic↗
PubMed1986

Use of a prognostic index in evaluation of liver transplantation for primary biliary cirrhosis.

In the Cambridge/King's College Hospital program, one of the main criteria for recommendation of a liver transplant for a patient with primary biliary cirrhosis (PBC), as in other types of end-stage liver disease, has been the overall assessment that survival was likely to be less than one year. In the present study, a recently developed prognostic model, based on six variables, was used retrospectively to estimate the likely survival without transplantation of the first 29 patients receiving a transplant for PBC. Median estimated survival time for the complete group of patients was five months and in only four patients was survival in the absence of transplantation estimated to be more than one year. Comparison of actual survival curves after transplantation with the estimated survival in the absence of such a procedure shows that, despite an initial higher mortality related to surgery and the immediate postoperative period, grafting was associated with a statistically significant improvement in overall survival. No correlation between the outcome after transplantation and the severity of preexisting liver disease, (as assessed by the expected survival) could be determined, but further assessment of preoperative variables is warranted.

Adult↗
PubMed1986

Ethanol metabolism in the generation of new antigenic determinants on liver cells.

Antibodies directed against ethanol altered liver cell components have been detected in the serum of nearly 50% of patients with alcoholic liver disease although the pathogenetic mechanisms are unclear. The importance of ethanol metabolism in the generation of new antigenic determinants on liver cells was investigated by in vivo inhibition of alcohol or acetaldehyde dehydrogenase and an induced cytotoxicity assay. There was a significant reduction in cytotoxicity to hepatocytes isolated from rabbits treated with ethanol 1 g/kg when the metabolism of ethanol to acetaldehyde by alcohol dehydrogenase was inhibited. In contrast when the oxidation of acetaldehyde was inhibited by disulfiram cytotoxicity was significantly enhanced. These results show that ethanol metabolism is integral to the expression of the ethanol related determinant and suggest that an impaired ability to metabolism acetaldehyde could lead to the development of immunological reactions to alcohol altered liver membrane antigens.

Alcohol Oxidoreductases↗
PubMed1986

In vitro effect of cyclosporin A on immunoglobulin production and concanavalin A induced suppression in primary biliary cirrhosis.

The in vitro effect of Cyclosporin A on the regulation of immunoglobulin production was investigated in 16 patients with primary biliary cirrhosis. A significant improvement in concanavalin A induced suppression of IgG and IgM producing cells was observed after prior incubation of mononuclear cells with 300 ng/ml Cyclosporin A for 30 minutes. No effect was seen on spontaneous or pokeweed mitogen induced immunoglobulin production, nor on con A induced suppression if Cyclosporin A was added after 24 hours. Incubation of mononuclear cells with a variable dose of Cyclosporin A showed an effect only at 250-500 ng/ml. Higher and lower doses had no effect. This dose dependent effect of Cyclosporin A is likely to be related to a differential inhibitory effect on T helper and T suppressor cells and may underlie the clinical benefit being observed in current clinical trials.

Aged↗
PubMed1986

The effect of prednisolone in vitro on immunoglobulin production in primary biliary cirrhosis.

Immunoglobulin production and its regulation have been investigated in 36 untreated patients with primary biliary cirrhosis and 14 healthy controls. Using a haemolytic plaque assay, the number of cells spontaneously producing IgG or IgM was normal, while in contrast, proliferation of both IgG and IgM producing cells in the presence of pokeweed mitogen was impaired (P less than 0.01). There was in addition a defect of Con A induced suppression of proliferation of IgG and IgM producing cells (P less than 0.01), which was more marked in those with early disease than in those with advanced disease. In vitro incubation of mononuclear cells with prednisolone, 5 X 10(-8) M, corrected the defect of Con A induced suppression, but had no effect on spontaneous or pokeweed mitogen stimulated immunoglobulin production. Prednisolone was only effective if added prior to exposure to Con A. There is anecdotal evidence that corticosteroids may be beneficial in primary biliary cirrhosis and the results of the present study study suggest that further investigation of their role is warranted.

Adult↗
PubMed1985

Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients.

Four forms of piecemeal necrosis--biliary, lymphocytic, ductular, and fibrotic--were identified in 605 liver biopsy specimens from 209 patients with primary biliary cirrhosis. Whereas lymphocytic piecemeal necrosis, often associated with lobular hepatitis, was most common in stages 2 and 3 of the classical histologic staging, biliary piecemeal necrosis was frequent in all stages, except stage 1, and the fibrotic form appeared to be a late, mainly cirrhotic feature. In 77% of patients cholestatic features predominated, whereas hepatitic changes producing some histologic overlap with chronic active hepatitis occurred in the remaining patients. These patterns tended to be maintained throughout the course of the disease. Large hypocellular scars found in 36% and 59% of stage 3 and 4 specimens, respectively, appeared to be a characteristic feature of biliary disease. The prevalence of classical features was assessed. The analysis of sequential biopsy specimens from those patients who died showed that cirrhotic transformation, increasing cholestasis (in particular with prominent hyaline inclusions), abundance of coarse collagen bundles, and "halo" formation at the margins of the fibrous septa were associated with a poor prognosis. We were unable to show that the presence of granulomas is associated with a more favorable course of the disease.

Adult↗
PubMed1985

Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial.

The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%-90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a "prognostic index" for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis.

Actuarial Analysis↗
PubMed1985

Mononuclear cell complement receptor blockade in primary biliary cirrhosis.

Peripheral blood monocyte and lymphocyte receptors for Fc and C3b fragments were examined in vitro in patients with primary biliary cirrhosis and other chronic liver diseases using sheep red blood cells coated with anti-SRBC IgG1 (to detect Fc receptors) and with anti-SRBC IgM and complement (to detect C3b receptors). The number of C3b receptors detected on 100 monocytes was significantly lower in patients with primary biliary cirrhosis (23.0 +/- 12.0, mean +/- 1 SD) compared with normal controls (57.4 +/- 16.9) and other chronic liver disease (HBsAg negative chronic active hepatitis 62.0 +/- 17.0, alcoholic cirrhosis 50.9 +/- 4.0), while the number of Fc receptors detected on 100 monocytes was not significantly different in all the groups (primary biliary cirrhosis 72.8 +/- 28.6, chronic active hepatitis 74.7 +/- 14.0, alcoholic cirrhosis 58.0 +/- 13.5 and normal controls 69.6 +/- 19.9). When mononuclear cells isolated from normal individuals were pre-incubated with serum from patients with primary biliary cirrhosis before testing their receptor function there was a significant reduction in the number of C3b receptors detected per 100 monocytes (27.6 +/- 10.8) compared with pre-incubation with normal serum (72.0 +/- 18.0). This reduction in C3b-receptor function was again observed when the serum used for pre-incubation was depleted of circulating immune complexes; but when complement was further depleted from these sera, the number of C3b-receptors detected after pre-incubation was similar to normal values (64.0 +/- 11.8). Lymphocyte receptors showed a similar pattern of results. This implies a specific C3b receptor blockade on monocytes and lymphocytes from patients with primary biliary cirrhosis which appears to be because of blocking by serum factor(s) including complement fragments.

Adult↗
PubMed1985

Antibody mediated hepatocyte injury in methyl dopa induced hepatotoxicity.

To investigate the mechanisms underlying the hepatotoxicity induced by methyl dopa, we have examined sera from nine patients with liver damage following the use of the drug for evidence of sensitisation to drug altered liver cell membrane antigens using both immunofluorescence and antibody dependent cell mediated cytotoxicity. Five sera induced significant cytotoxicity to hepatocytes isolated from rabbits pretreated with methyl dopa after exposure to the mixed function oxidase inducer, Arachlor 1254. Sera from 10 patients on methyl dopa but with normal liver function and 32 patients with other drug and viral induced liver damage, gave normal cytotoxicity values. Two of the antibody positive sera gave a specific immunofluorescence pattern at the periphery of human hepatocytes when tested on liver biopsy specimens taken from patients taking methyl dopa. These findings are consistent with the view that immune mechanisms directed against drug associated antigens are involved in severe liver damage from methyl dopa administration and that metabolic activation of the drug is implicated in the generation of drug associated antigen. The need for a combination of immune and metabolic factors may explain the rarity of this condition.

Aged↗
PubMed1985

Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis.

One hundred and eighty nine patients with primary biliary cirrhosis were entered into a double blind, placebo controlled randomised trial starting in January 1978 to assess the therapeutic value of d-penicillamine 1200 mg daily. Eighteen of the 98 patients receiving d-penicillamine and 22 of the 91 placebo treated patients died during the study. Thirty six per cent of those on d-penicillamine and 8% of those on placebo were withdrawn from the study. No difference in overall survival was noted between the two groups of patients whether the results were analysed for the entire period of observation or only during the period in which the patients were receiving therapy. The mortality rate of those receiving d-penicillamine in histological stage I to II, however, was one third of that of the placebo group although this difference did not reach statistical significance. Using the occurrence rate ratio as the statistical method of analysis, no effect of d-penicillamine was noted on any clinical, biochemical or histological features examined, except the serum alanine aminotransferase activity which was greater in those on active treatment. In this trial we have been unable to establish any therapeutic benefit from the drug.

Clinical Trials as Topic↗
PubMed1985

In vitro studies on the mechanism of increased serum IgM levels in primary biliary cirrhosis.

To evaluate the mechanisms underlying the increase in serum IgM in primary biliary cirrhosis (PBC) studies were designed to examine IgM production in vitro and to assess the relative contribution of intrinsic B cell activity and immunoregulatory T cell balance to IgM synthesis. The number of peripheral blood lymphocytes (PBL) producing IgM (spontaneous and pokeweed mitogen (PWM) stimulated) at the end of a seven day culture period was similar in PBC patients and control subjects while the amount of IgM synthesized (spontaneous and PWM stimulated) during this period was significantly greater in the patient group, implying that the amount of IgM produced per B cell was increased in PBC. Co-culture of autologous and allogeneic T and B lymphocytes and irradiation of T lymphocytes from patients and normal subjects clearly implicated abnormal suppressor T cell function, rather than autonomous B cell hyperactivity, as the cause of the increased IgM synthesis. Direct studies of T cell function indicated that although concanavalin A (Con A) activated suppressor cells inhibited proliferation of IgM producing B cells in the majority of PBC patients, they were unable to inhibit IgM synthesis. The demonstration of a disparity between IgM synthesis and the proliferation of IgM-producing B cells, together with the observation that the abnormality of T cell function is largely confined to the control of IgM secretion, is consistent with the presence of at least two different suppressor subpopulations regulating IgM production. In PBC the main suppressor cell abnormality seems to affect regulation of IgM secretion rather than B cell proliferation.

B-Lymphocytes↗
PubMed1985

Long-term use of cyclosporin in liver grafting.

The clinical course of 29 liver graft recipients in the Cambridge/King's College Hospital series who have received cyclosporin A (CyA) for up to five years (median 40 months) was analysed with particular reference to the immunosuppressive effectiveness and adverse effects of the drug. Eight patients had been maintained on prednisolone and azathioprine for two to six years before treatment was changed to cyclosporin A and the remainder were started on cyclosporin A after operation. Results in both groups over a one to five year study period are similar, and showed that cyclosporin A was effective in maintaining adequate immunosuppression, allowing complete withdrawal of prednisolone in 16 patients. Episodes of rejection were observed in only three patients and in two of these it was of the chronic 'vanishing bile duct' variety. Some evidence of nephrotoxicity (serum creatinine greater than 150 mumol/l) occurred in 72 per cent (21 of 29 patients) but it was necessary to discontinue treatment in only two. Hypertension, occasionally of sudden onset, was found in nine patients and led to the withdrawal of the drug in two. Additional hypotensive drug treatment was required in five. In one other patient cyclosporin A was discontinued on account of severe headaches. Cyclosporin A was withdrawn in two further patients. Withdrawal led to considerable risk of acute rejection and increased doses of corticosteroids as well as substitution of azathioprine were required at that time.

Adolescent↗
PubMed1985

[Centrolobular liver cell necroses following occupational halothane contact. Association with antibodies to halothane altered liver cell components].

A report is given on a 24 year old nurse, who developed two episodes of fever, chills and malaise with high serum enzyme levels and histologic proof of extensive centrolobular hepatic necrosis in association with vocational halothane exposure in the operating theatre. A cause-effect relationship was suggested by the demonstration of antibodies against halothane-altered hepatocyte membrane components. Also, there was no indication of other known causes of a cytotoxic liver reaction. In certain predisposed individuals, halothane even in subanaesthetic concentrations is apparently able to induce liver cell damage. Only six further reports on such liver injuries in medical personnel could be found in the literature.

Adult↗
PubMed1984

An enzyme-linked immunosorbent assay for detection of antibodies against halothane-altered hepatocyte antigens.

Patients with massive liver cell necrosis that may follow halothane anaesthesia have a high incidence of circulating antibodies against halothane-induced hepatocyte antigens. In order to provide an objective and quantitative method for the detection of these antibodies, an enzyme-linked immunosorbent assay has been developed. Sera, after absorption with normal rabbit liver microsomal fraction, are tested for binding to microsomal fractions from control and halothane-pretreated rabbits. Those containing antibodies against halothane-induced determinants give significantly enhanced binding to halothane-altered fractions; this specificity was verified by absorption experiments. Using this method, halothane-related antibodies were detected in sera from 16/24 patients with halothane-associated liver failure, at titres ranging from 1:100 to 1:25600. Such antibodies were not detectable in sera from 26 normal blood donors, 5 healthy anaesthetists, 12 patients who had received multiple halothane anaesthetics but had normal liver function tests and 32 patients with a variety of other liver diseases. This rapid and reproducible assay should be of value for the detection of antibodies and for detailed investigation of patient antibody responses, and also for characterization of the route of production and metabolism of the antigen.

Absorption↗