A.M.L. Lever

NON-A, NON-B HEPATITIS OCCURRING IN AGAMMAGLOBULINAEMIC PATIENTS AFTER INTRAVENOUS IMMUNOGLOBULIN

Acute non-A, non-B hepatitis developed in twelve patients with primary hypogammaglobulinaemia during treatment with intravenous gammaglobulin prepared by Cohn fractionation of pooled plasma. The illness was clinically and histologically identical to the short-incubation non-A, non-B, hepatitis observed in haemophilic patients receiving factor VIII concentrates. Most of the patients were symptomless, but 10 months after onset ten of the twelve still had abnormal liver function. The occurrence of non-A, non-B hepatitis in agammaglobulinaemics indicates that humoral mechanisms are not essential for production of hepatocyte necrosis in this infection. This outbreak emphasises the need for a screening test to identify the agent in blood products, and shows that Cohn fractionation of plasma does not always inactivate the agent. Furthermore, the finding that the virus can be transmitted in IgG concentrates suggests either that the general population has a very low level of antibodies to the putative virus or that such antibodies are not virus-neutralising.

ALPHA-INTERFERON THERAPY FOR NON-A, NON-B HEPATITIS TRANSMITTED BY GAMMAGLOBULIN REPLACEMENT THERAPY

Three hypogammaglobulinaemic patients with non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy were treated with lymphoblastoid alpha-interferon. All showed a striking improvement in serum aminotransferases after the start of each course of treatment.

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.

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.

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)

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

SummaryWe 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 (37), 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. As in the infection acquired in adult life, the presence in the hepatitis B virus genome of an interferon sensitive site, homologous to that found in the hepatocyte genome, will influence the biological response to interferon. It is now evident that there are several mechanisms underlying the chronic carrier state and that in different patients at varying stages of the infection, alternative approaches to therapy may be required.ZusammenfassungDie Behandlungsergebnisse mit Adenin-Arabinosid, Adenin-Arabinosid-Monophosphat und Lymphoblasten-Interferon bei mehr als 100 HBV-Trägern wurden ausgewertet. Bei der Gruppe homosexueller Carrier erwiesen sich Adenin-Arabinosid und sein Monophosphat als wirkungslos. Dagegen war in dieser Gruppe mit Lymphoblasten-Interferon eine Ansprechrate von mehr als 50% zu verzeichnen. Möglicherweise sind immunsuppressive Eigenschaften von Adenin-Arabinosid für seine fehlende Wirksamkeit bei dieser Gruppe verantwortlich. Bei heterosexuellen HBV-Trägern war sowohl Adenin-Arabinosid als auch Lymphoblasten-Interferon bei etwa 50% bis 60% der Fälle wirksam. Doch fanden sich Unterschiede in den Ansprechraten verschiedener ethnischer Gruppen. Im Gegensatz zu Patienten aus Nordeuropa und den Mittelmeerländern sprachen Patienten aus dem fernen Osten auf die Therapie nicht an. Dies könnte der Ausdruck von mindestens zwei verschiedenen Pathomechanismen für die Entstehung des chronischen Trägertums sein. Bei 5% bis 10% der Erwachsenen findet sich ein relativer Mangel an Alpha-Interferon-Produktion, und dieser Mangel läßt sich bei der Mehrzahl der HBV-Carrier aus Westeuropa nachweisen. Bei diesen Patienten stellt die Interferongabe eine Substitutionstherapie dar und erzielt ausgezeichnete Ergebnisse, wenn die Behandlung in der Frühphase der Erkrankung erfolgt. Mit zunehmender Krankheitsdauer integriert das Virus offensichtlich in Loci, die für das Ansprechen auf Interferon verantwortlich sind, und unterdrückt so die Reaktionsfähigkeit der Zelle auf Interferon. Bei Patienten, die unter der Geburt infiziert werden, scheint transplazentar übertragenes anti-HBc die Immunantwort zu modulieren; infolgedessen und wegen der Unreife des Immunsystems in diesem Alter können infizierte Zellen nicht lysiert werden. Diese Patienten haben von der Interferontherapie keinen Gewinn, bei ihnen wäre eine Form von immunologischer Manipulation erforderlich. Wie bei der im Erwachsenenalter erworbenen Infektion übt die Anwesenheit eines Interferon-sensiblen Locus im Hepatitis B-Virus-Genom, der dem im Hepatozyten-Genom gefundenen Locus homolog ist, einen Einfluß auf das biologische Ansprechen auf Interferon aus. Es ist inzwischen erwiesen, daß für die Entstehung des chronischen Trägertums mehrere verschiedene Pathomechanismen vorhanden sind und daß für verschiedene Stadien der Infektion bei verschiedenen Patienten unterschiedliche Therapieansätze nötig sein können.

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@@@Wirksamkeit von Adenin-Arabinosid und Lymphoblasten-Interferon bei chronischem Hepatitis B-Virus-Trägertum. Übersicht über die am Royal Free Hospital durchgeführten Studien. Identifizierung von Faktoren, die die Ansprechrate beeinflussen

SummaryWe 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 (37), 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. As in the infection acquired in adult life, the presence in the hepatitis B virus genome of an interferon sensitive site, homologous to that found in the hepatocyte genome, will influence the biological response to interferon. It is now evident that there are several mechanisms underlying the chronic carrier state and that in different patients at varying stages of the infection, alternative approaches to therapy may be required.ZusammenfassungDie Behandlungsergebnisse mit Adenin-Arabinosid, Adenin-Arabinosid-Monophosphat und Lymphoblasten-Interferon bei mehr als 100 HBV-Trägern wurden ausgewertet. Bei der Gruppe homosexueller Carrier erwiesen sich Adenin-Arabinosid und sein Monophosphat als wirkungslos. Dagegen war in dieser Gruppe mit Lymphoblasten-Interferon eine Ansprechrate von mehr als 50% zu verzeichnen. Möglicherweise sind immunsuppressive Eigenschaften von Adenin-Arabinosid für seine fehlende Wirksamkeit bei dieser Gruppe verantwortlich. Bei heterosexuellen HBV-Trägern war sowohl Adenin-Arabinosid als auch Lymphoblasten-Interferon bei etwa 50% bis 60% der Fälle wirksam. Doch fanden sich Unterschiede in den Ansprechraten verschiedener ethnischer Gruppen. Im Gegensatz zu Patienten aus Nordeuropa und den Mittelmeerländern sprachen Patienten aus dem fernen Osten auf die Therapie nicht an. Dies könnte der Ausdruck von mindestens zwei verschiedenen Pathomechanismen für die Entstehung des chronischen Trägertums sein. Bei 5% bis 10% der Erwachsenen findet sich ein relativer Mangel an Alpha-Interferon-Produktion, und dieser Mangel läßt sich bei der Mehrzahl der HBV-Carrier aus Westeuropa nachweisen. Bei diesen Patienten stellt die Interferongabe eine Substitutionstherapie dar und erzielt ausgezeichnete Ergebnisse, wenn die Behandlung in der Frühphase der Erkrankung erfolgt. Mit zunehmender Krankheitsdauer integriert das Virus offensichtlich in Loci, die für das Ansprechen auf Interferon verantwortlich sind, und unterdrückt so die Reaktionsfähigkeit der Zelle auf Interferon. Bei Patienten, die unter der Geburt infiziert werden, scheint transplazentar übertragenes anti-HBc die Immunantwort zu modulieren; infolgedessen und wegen der Unreife des Immunsystems in diesem Alter können infizierte Zellen nicht lysiert werden. Diese Patienten haben von der Interferontherapie keinen Gewinn, bei ihnen wäre eine Form von immunologischer Manipulation erforderlich. Wie bei der im Erwachsenenalter erworbenen Infektion übt die Anwesenheit eines Interferon-sensiblen Locus im Hepatitis B-Virus-Genom, der dem im Hepatozyten-Genom gefundenen Locus homolog ist, einen Einfluß auf das biologische Ansprechen auf Interferon aus. Es ist inzwischen erwiesen, daß für die Entstehung des chronischen Trägertums mehrere verschiedene Pathomechanismen vorhanden sind und daß für verschiedene Stadien der Infektion bei verschiedenen Patienten unterschiedliche Therapieansätze nötig sein können.

Production of a Partially Acid Labile Alpha Interferon in Cytomegalovirus Pneumonitis

Interstitial pneumonitis is a common complication of organ transplantation, especially bone marrow transplantation, and the pathogen most frequently isolated is cytomegalovirus (CMV) 1. Studies from a murine model using murine CMV (MCMV) have suggested that MCMV interstitial pneumonitis may have an immunopathological basis 2,3. The ultrastructural pathology of CMV pneumonitis has been reported to be identical to that seen in interstitial lung disease occurring in patients with collagen vascular diseases such as systemic lupus erythrematosus (SLE)4. Patients with SLE have been found to have circulating levels of both an acid labile and an acid stable α interferon 5 ,6 and it has been postulated this may be involved in the immunopathology of SLE 5 ,7. MCMV has been shown to induce partially acid labile α interferon after in vivo infection 8 , 9, and in man this type of interferon is seen in patients with the acquired immunodeficiency syndrome (AIDS)10 ,11; who frequently have infections with CMV12. We have therefore searched for the presence of acid labile and acid stable interferons in the bronchoalveolar lavage fluid of patients with proven CMV pneumonitis, in order to see whether this might aid in understanding its pathogenesis. In addition, as specific antigenic or mitogenic stimulation of lymphocytes results in the production of γ interferon, we have also looked for the presence of this type of interferon in the lavage fluid. Furthermore, we have analysed whether the presence or absence of such interferons in the lavage fluid has any diagnostic or prognostic value for CMV pneumonitis.