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Biomedical subjects

M Pignatelli

Publications and source records attributed to M Pignatelli.

At least 127 records · Page 7Linked to original sources
PubMed1987

Characterisation of the polymerised and monomeric human serum albumin binding sites on hepatitis B surface antigen.

Receptors for polymerised human albumin are present on the pre-S sequence of the envelope protein of HBV and on the hepatocyte membrane and are thought to be involved in uptake of the virus by hepatocytes. Using a solid phase radioimmunoassay we demonstrate binding of HBsAg to polymerised human serum albumin (pHSA) in both HBe antigen-positive and -negative patients, and this binding is linearly related to the HBsAg titre in both groups. There are probably several modes of interaction between HBsAg and pHSA. Here we show that pHSA binds to the 22,000-dalton polypeptide of HBsAg, which does not contain the pre-S sequence. This pHSA-HBsAg interaction is inhibited by physiological concentrations of human serum albumin, suggesting that the albumin known to be present in the envelop of HBsAg plays a role in this binding. The inhibition of pHSA/HBsAg interaction by native albumin suggests that this interaction is probably not an important mechanism of virus uptake during infection of hepatocytes.

Animals↗
PubMed1987

A review of the efficacy of adenine arabinoside and lymphoblastoid interferon in the Royal Free Hospital studies of hepatitis B virus carrier treatment: identification of factors influencing response rates.

We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However in this group, lymphoblastoid interferon will produce a response in over 50% of cases. This lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferons are effective in approximately 50% to 60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least two mechanisms by which the chronic carrier state may arise. In 5% to 10% of adults, a relative deficiency of alpha interferon production exists, and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and, along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)

Arabinonucleotides↗
PubMed1987

Cytotoxic T-cell responses to the nucleocapsid proteins of HBV in chronic hepatitis. Evidence that antibody modulation may cause protracted infection.

The nucleocapsid antigens (HBc and HBe) are present on the membranes of HBV-infected hepatocytes from HBV carriers. In autologous cytotoxicity experiments we demonstrate that cytotoxic T cells sensitised to the nucleocapsid proteins of hepatitis B are present in HBe antigen-positive HBV carriers with chronic hepatitis and can be blocked by monoclonal anti-HBc and anti-HBe. Passive immunisation of chimpanzees with monoclonal anti-HBc and anti-HBe offers no protection against HBV infection but in both cases leads to an unusually prolonged hepatitis probably by modulation of HBc and HBe antigen display on the hepatocytes. High-titre anti-HBc in the circulation of HBe antigen-positive patients probably modulates the former protein making HBe the important target antigen for cytotoxic T cells mediating liver damage in chronic carriers. These data also support the hypothesis that passive transfer of IgG anti-HBc across the placenta may be one major factor promoting development of persistent infection in neonates infected from carrier mothers.

Animals↗
PubMed1987

Expression of major histocompatibility complex class II antigens on bile duct epithelium in patients with hepatic graft-versus-host disease after bone marrow transplantation.

We studied the expression of major histocompatibility complex (MHC) class II antigens in liver biopsies taken from ten patients with clinical and biochemical evidence of liver damage after bone marrow transplantation. In all six patients who had histologically confirmed graft-versus-host disease, MHC class II antigens were detected on intrahepatic bile ducts. In four patients with no histological features of graft-versus-host disease, MHC class II antigens were not detected. In controls, a positive reaction for bile duct MHC class II antigens was only detected in the patients with primary biliary cirrhosis. Characterisation of the lymphocytes surrounding the bile ducts showed a prevalence of Leu 3+ cells in graft-versus-host disease and primary biliary cirrhosis. We propose that the aberrant expression of class II antigens on bile duct epithelium cells may play a role in the pathogenesis of graft-versus-host disease. A similar pattern in primary biliary cirrhosis may suggest a common pathogenetic mechanism.

Adult↗
PubMed1987

The immune response to hepatitis B virus.

Cell-mediated immune response to nucleocapsid determinants, including HBcAg and HBeAg, are important in the clearance of HBV-infected hepatocytes. This process is modulated by interferon and humoral responses to these antigens. Antibodies to the envelope proteins contribute to protective immunity, but the relative importance of pre-S and S determinants in evoking a response and the relative contributions of these antibodies in virus neutralization remains unclear. It is known, however, that antibodies binding to the RFHBs1 epitope on the HBs sequence 124-137 are capable of protecting against further infection and are present in convalescent subjects and in recipients of the plasma-derived and recombinant hepatitis B vaccines. Detailed analysis of the specificity of the anti-HBs response in vaccinees shows it to be qualitatively similar to that seen during recovery from natural infection.

Animals↗
PubMed1986

Hepatitis A virus replication in tamarins and host immune response in relation to pathogenesis of liver cell damage.

Hepatitis A virus (HAV) shedding in the faeces, appearance of HAV-Ag (antigen) in the liver, and development of humoral immunity to HAV have been studied in experimentally infected tamarins. The appearance of liver damage measured by transaminase elevation and histology, in relation to the above variables, suggests that the virus is not cytopathic and the immune system contributes to the production of liver cell damage. Preliminary data suggest that HAV replication may occur in the mucosa of the small intestine and in the liver.

Animals↗
PubMed1986

Homology between HBV-DNA and a sequence regulating the interferon-induced antiviral system: possible mechanism of persistent infection.

Treatment of hepatitis B virus (HBV)-infected hepatocytes with lymphoblastoid alpha-interferon (IFN) leads to an increased expression of the core antigen (HBcAg) and reduced expression of surface antigen (HBsAg). We have identified the presence of a nucleotide sequence at the start of the HBc gene in the hepatitis B virus genome similar to a consensus sequence known to occur upstream from genes induced by IFN in mammalian cells. It is possible that interferon influences the expression of the viral genes because of the presence of this homologous sequence. This sequence in the viral genome may determine the site of integration of the virus and could influence the ability of the cell containing the integrated viral sequence to respond to interferon. This "neutralisation" of the interferon system by viral integration might not only facilitate persistent infection but might also adversely affect response to alpha-interferon therapy.

Biopsy↗
PubMed1986

T lymphocyte subsets implicated in cytotoxicity in autologous hepatocytes in chronic active hepatitis patients with active viral replication.

We investigated inhibitory effect of various monoclonal antibodies on T-cell-mediated cytotoxicity against autologous hepatocytes in 24 patients with hepatitis B surface antigen/hepatitis B e antigen (HBsAg/HBeAg)-positive chronic active hepatitis. A significant reduction of cytotoxicity index occurred after preincubation of T lymphocytes with anti-Leu 7 (killer-natural killer cells), D1/12 (Ia-positive cells), 5/9 (restricted helper/inducer cells), and MLR4 ("activated" and radiosensitive helper cells) monoclonal antibodies (MAb). Anti-Leu 2a (cytotoxic/suppressor cells) and anti-Leu 3a (helper/inducer cells) MAb did not affect cytotoxic activity. This finding supports the hypothesis that the T cytotoxic reaction in this in vitro system is probably due to two mechanisms: first, spontaneous cell membrane cytotoxicity sustained by anti-Leu-7-positive lymphocytes; and second, specific cytotoxicity mediated by activated Ia-positive cells. We also found that the presence of helper/inducer cells (5/9 positive) appears to be a prerequisite for the cytotoxic reaction.

Adult↗
PubMed1986

Human lymphoblastoid interferon. In vitro and in vivo studies in hepatocellular carcinoma.

We have examined the growth inhibitory effects of human lymphoblastoid interferon (IFN) on the human hepatocellular carcinoma (HCC) cell line PLC/PRF/5. In vitro, PLC/PRF/5 cells were sensitive to the antiproliferative effects of IFN, growth inhibition being noted at concentrations as low as 1.25 i.u. ml-1. Athymic mice with xenografted tumours derived from the PLC/PRF/5 cell line were treated daily with IFN or a saline control. An IFN dose of 2 X 10(5) i.u./day was found capable of significantly slowing tumour growth rate and prolonging mouse survival. Further studies to examine the mechanisms involved in growth inhibition in vivo demonstrated that IFN was capable of inducing the activity of the enzyme 2,5-oligoadenylic acid (2,5 A) synthetase, a potent inhibitor of protein synthesis, in tumour xenografts but not in mouse tissue, and that IFN significantly enhanced the membrane display of HLA class I glycoproteins on tumour cells, though histology did not reveal any increase in tumour infiltration by host lymphocytes. We conclude that IFN exerts potent growth inhibitory effects on the HCC cell line PLC/PRF/5 both in vitro and in vivo and its mode of action in this animal model system appears to be predominantly mediated by a direct antiproliferative effect on tumour cells.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Identification of factors influencing response rate to antiviral therapy of chronic hepatitis B virus infection. A review of the efficacy of adenine arabinoside and lymphoblastoid interferon in the Royal Free Hospital studies.

We have reviewed the results of treating over 100 HBV carriers with adenine arabinoside, adenine arabinoside monophosphate and lymphoblastoid interferon. In the homosexual group of carriers, adenine arabinoside and its monophosphate have no value. However, in this group, lymphoblastoid interferon will produce a response in over 50% of cases. The lack of effectiveness of adenine arabinoside monophosphate in this group may stem from its immunosuppressant properties. In heterosexual carriers both adenine arabinoside monophosphate and lymphoblastoid interferon are effective in approximately 50-60% of cases. However, the response rate is different in the various racial groups. Northern European and Mediterranean people appear to respond whereas those from the Far East do not. This may reflect the fact that there are at least 2 mechanisms by which the chronic carrier state may arise. In 5-10% of adults, a relative deficiency of alpha-interferon production exists and this defect is found in the majority of HBV carriers in Western Europe. In these, interferon acts as a replacement therapy and excellent results may be obtained if the patient is treated early in the course of the disease. It would appear that as the duration of the infection increases, the virus may integrate into interferon-reactive consensus sites and prevent the cell from responding to interferon. In patients infected at birth, transplacental anti-HBc appears to modulate the immune response and along with immaturity of the immune system at this age, results in failure to lyse infected cells. These patients do not benefit from interferon treatment: some form of immune manipulation is required.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1986

Virus-neutralizing antibodies to hepatitis B virus: the nature of an immunogenic epitope on the S gene peptide.

Using a murine monoclonal antibody (RF-HBs-1) which has been shown to be capable of neutralizing both ad and ay subtypes of hepatitis B virus (HBV), we have devised a competitive inhibition assay to measure the presence of virus-neutralizing antibodies in the sera of patients who have recovered from acute type B hepatitis. The majority of patients have this antibody in their serum. We also show that this antibody inhibits the binding of polymerized human serum albumin (pHSA) to the pHSA receptor site of the HBV particle, which has been proposed as an important site for the entry of HBV into liver cells. We have demonstrated that the epitope recognized by this antibody is dependent on the linkage of 24,000 and 28,000 mol. wt. polypeptides via a disulphide bond. This conformational determinant in the coat of the virus which is part of or near to the pHSA binding site is important in evoking a virus-neutralizing response.

Antibodies, Monoclonal↗
PubMed1986

Relationship of HLA protein display to activation of 2-5A synthetase in HBe antigen or anti-HBe positive chronic HBV infection.

In this study we have examined the density of HLA class I protein display on the hepatocytes of patients with HBe antigen (HBeAg) or anti-HBe (HBeAb) positive chronic hepatitis B virus (HBV) infection and related this to the level of interferon activation of these cells determined by measuring hepatic oligo 2-5A synthetase activity. In HBeAg positive patients the density of HLA class I (HLA-I) protein was not significantly increased above that found in uninfected liver, but levels of 2-5A synthetase were twice normal. In anti-HBe positive patients, HLA-I density was markedly increased in the presence of normal 2-5A synthetase activity. These data are consistent with type I (alpha or beta) interferon activation of the hepatocytes in HBeAg positive patients and type II (gamma) interferon activity in anti-HBe positive subjects.

2',5'-Oligoadenylate Synthetase↗
PubMed1985

Viruses and immune reactions in the liver.

The immunopathology of hepatitis B and delta virus infections of the liver are reviewed. It is clear there are several antigen/antibody systems of importance in acute and chronic HBV infection. Antibodies to HBs, HB core/HBe and antibodies to Dane specific determinants are involved in virus neutralisation. Elimination of virus infected hepatocytes is dependent on recognition of viral determinants in association with HLA proteins on the infected hepatocytes by cytotoxic T cells. The HLA protein display is modulated by exposure to interferon and may regulate the cytotoxic T cell and NK lytic processes. During chronic HBV infection there is evidence of failure of interferon activation of the infected liver cells so that viral protein synthesis is not decreased and there is no enhancement of HLA protein display. These complex interactions between the virus and the immune system determine the heterogeneity of the clinical syndromes seen in patients infected with this agent. The delta virus replicates only in patients with co-existent HBV infection. The agent is cytopathic and therefore always produces liver disease. When there is delta virus superinfection in a carrier of chronic HBV, there is an acceleration of the rate of progression of the liver disease. The presence of delta infection results in IgM and IgG anti-delta responses.

Cytopathogenic Effect, Viral↗