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Biomedical subjects

B Rehermann

Publications and source records attributed to B Rehermann.

34 records · Page 2Linked to original sources
PubMed1997

Immunopathology of hepatitis C.

Hepatitis C virus (HCV) infection becomes persistent in the majority of instances in the face of a humoral and cellular immune response, and persistent HCV infection is associated with chronic hepatitis. In particular, cytotoxic T lymphocytes (CTL), crucial in the eradication of virus-infected cells, have been observed in the liver and the peripheral blood of chronically infected patients, suggesting that CTL cannot completely eliminate the virus, and may contribute to chronic liver injury. In this review, the potential host and the viral factors involved in the pathogenesis of chronic HCV infection will be discussed with emphasis on the HLA-A2 restricted peripheral blood CTL response and its relationship to liver disease and viral load.

Amino Acid Sequence↗
PubMed1996

Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) are present in the peripheral blood and liver of chronically infected patients. The current study was performed to study the relationship between the strength of the CTL response, liver disease severity, and viral load. The results may be summarized as follows: first, using CTL precursor frequency (CTLpf) analysis to quantitate the peripheral blood CTL response, chronically infected patients were less strongly sensitized to a panel of well-defined HCV epitopes than they were to an epitope within the influenza matrix protein. Second, HCV-specific CTLpf did not correlate with disease activity or viral load in the majority of patients on a cross-sectional basis, although it did increase in three patients concomitant with sharp increases in liver disease. Finally, interferon therapy did not enhance the CTLpf against the HCV epitopes studied in these patients, indicating that its antiviral effect is independent of the CTL response. Since the HCV-specific CTLpf in the blood is actually quite low, the CTL may contribute to ongoing liver disease in these patients while being quantitatively inadequate to destroy all of the infected hepatocytes, thereby facilitating HCV persistence and contributing to chronic liver disease.

Adult↗
PubMed1996

Long-lasting memory T cell responses following self-limited acute hepatitis B.

The molecular and cellular basis of long-term T cell memory against viral antigens is still largely undefined. To characterize anti-viral protection by memory T cells against non-cytopathic viruses able to cause acute self-limited and chronic infections, such as the hepatitis B virus (HBV), we studied HLA class II restricted responses against HBV structural antigens in 17 patients with acute hepatitis B, during the acute stage of infection and 2.2 to 13 yr after clinical resolution of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectable in all patients during the acute phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; b) long-lasting T cell responses were sustained by CD45RO+T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparable to that observed in the acute stage of infection and, usually, higher than in patients with chronic HBV infection; d) the same amino acid sequences were recognized by T cells in the acute and recovery phases of infection; and e) HBV-DNA was detectable by nested-PCR in approximately half of the subjects. to conclusion, our results show that vigorous anti-viral T cell responses are detectable in vitro several years after clinical recovery from acute hepatitis B. Detection of minute amounts of virus in some recovered subjects suggests that long-term maintenance of an active anti-viral T cell response could be important not only for protection against reinfection but also for keeping the persisting virus under tight control.

Acute Disease↗
PubMed1996

Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection.

Clearance of the hepatitis B virus (HBV) during acute hepatitis is associated with a strong, polyclonal, multispecific cytotoxic T lymphocyte (CTL) response to the viral envelope, nucleocapsid and polymerase proteins that persists for decades after clinical recovery. In contrast, chronically infected patients usually fail to mount a strong CTL response to this virus. In this study we demonstrate that chronically infected patients who experience a spontaneous or interferon-induced remission develop a CTL response to HBV that is similar in strength and specificity to patients who have recovered from acute hepatitis. The results suggest that specific immunotherapeutic enhancement of the CTL response to HBV should be possible in chronically infected patients, and that it could lead to viral clearance in these individuals with resolution of chronic liver disease.

Acute Disease↗
PubMed1996

Serological pattern of hepatitis C virus recurrence after liver transplantation.

BACKGROUND/AIMS: Hepatitis C infection is characterized by a high incidence of liver cirrhosis, frequently requiring liver transplantation. After orthotopic liver transplantation, recurrence of hepatitis C virus infection is common, but often difficult to differentiate from allograft rejection. In this context the role and diagnostic value of hepatitis C virus-associated markers like the anti-GOR response have not yet been determined. In this study we analyzed the time course of hepatitis C virus recurrence in hepatitis C virus-infected patients who underwent liver transplantation because of end-stage cirrhosis or acute liver failure. METHODS: We evaluated the serological pattern and diagnostic significance of anti-HCV, anti-HCV-IgM, anti-HCV-core, anti-HCV-core 5-27, anti-GOR, anti-GOR-IgM and HCV-RNA in serial serum samples during hepatitis C virus recurrence with or without allograft rejection up to 5-64 months after orthotopic liver transplantation. For comparison, we also studied these markers in serial serum samples from previously uninfected patients who acquired hepatitis C virus-infection during or shortly after orthotopic liver transplantation. Hepatitis C virus-infected patients who had undergone orthotopic liver transplantation were identified by screening pre-transplant sera from 235 patients for the presence of anti-HCV (2nd generation ELISA) and serum HCV-RNA (reverse transcription polymerase chain reaction). RESULTS: Of 218 patients transplanted for end-stage liver cirrhosis, 65 (30%) were anti-HCV positive and 33 (15%) were HCV-RNA positive, while only one of 17 patients (6%) transplanted for acute liver failure was found to be anti-HCV positive without detectable HCV-RNA. Fifty-two hepatitis C virus-infected patients were studied serially before and after liver transplantation: 46 patients (89%) showed recurrent anti-HCV antibodies within 3 months and 51 patients (98%) within 42 months after orthotopic liver transplantation. Serum HCV-RNA was detected in 39 patients (75%) within 3 months and in 44 patients (85%) within 42 months after orthotopic liver transplantation. In the patients studied serially during hepatitis C virus-recurrence, anti-GOR antibodies displayed the same serological profile as hepatitis C virus antibodies, i.e. a decrease after orthotopic liver transplantation and slowly rising titers when HCV-RNA became detectable again. De novo infection with hepatitis C virus as studied in four patients produced a significant peak of anti-HCV titers accompanied or followed by an increase in anti-GOR titers, indicating that the immune response to GOR-autoantigen is triggered by the hepatitis C virus. No significant diagnostic difference between anti-GOR and anti-HCV was noted during hepatitis C virus recurrence and allograft rejection.

Amino Acid Sequence↗
PubMed1996

Immunopathogenesis of viral hepatitis.

More than 500 million people world-wide suffer from viral hepatitis which can be caused by a variety of distinct infectious agents. The spectrum of disease, which ranges from acute self-limited hepatitis to liver cirrhosis, not only reflects the different biological properties and pathogenicity of the hepatitis viruses, but is also the result of the specific interaction between each virus and the immune system of the infected host. The immune response plays a crucial role in the elimination of the infecting virus as well as in disease pathogenesis and is described in detail for acute and chronic hepatitis B and C virus infection. Acute hepatitis B virus infection is characterized by a vigorous, polyclonal cytotoxic T lymphocyte response against HBV that is not readily detectable in patients with chronic hepatitis B, suggesting that resolution of disease is mediated by the HBV-specific CTL response in these patients. Because traces of virus as well as HBV-specific CTL can persist for decades after clinical recovery, continuous priming of new CTL by minute traces of virus is thought to protect from reactivation of disease. In contrast, the hepatitis C virus causes chronic liver disease despite a polyclonal and multispecific immune response, suggesting that distinct immunological and viral mechanisms determine the different clinical outcome of HBV and HCV infection. Their implications for the development of immunomodulatory vaccines to cure patients with chronic viral hepatitis are discussed.

Adjuvants, Immunologic↗
PubMed1996

The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response.

It is widely believed that the hepatitis B virus (HBV) is completely cleared by antiviral antibodies and specific cytotoxic T lymphocytes (CTLs) during acute viral hepatitis. We now demonstrate that traces of HBV are often detectable in the blood for many years after clinical recovery from acute hepatitis, despite the presence of serum antibodies and HBV-specific CTLs, which can be present at acute-stage levels. The strength of the CTL response to HBV following clinical recovery correlates with persistence of HBV DNA. It is of particular interest that HBV-specific CTLs from patients studied up to 23 years after clinical and serological recovery expressed activation markers (HLA-DR, CD69) indicating recent contact with antigen. These results suggest that sterilizing immunity to HBV frequently fails to occur after recovery from acute hepatitis and that traces of virus can maintain the CTL response for decades following clinical recovery, apparently creating a negative feedback loop that keeps the virus under control, perhaps for life.

Acute Disease↗
PubMed1996

Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients.

Cytotoxic T lymphocytes (CTL) are thought to control hepatitis B virus (HBV) infection, since they are readily detectable in patients who clear the virus whereas they are hard to detect during chronic HBV infection. In chronic hepatitis C virus (HCV) infection, however, the virus persists in the face of a CTL response. Indeed, most infected patients respond to one or more HCV-1 (genotype 1a)-derived CTL epitopes in the core, NS3, and NS4 proteins, and the CTL response is equally strong in patients infected by different HCV genotypes, suggesting broad cross-reactivity. To examine the effect of the HCV-specific CTL response in patients with chronic hepatitis C on viral load and disease activity, we quantitated the strength of the multispecific CTL response against 10 independent epitopes within the HCV polyprotein. We could not detect a linear correlation between the CTL response and viral load or disease activity in these patients. However, the CTL response was stronger in the subgroup of patients whose HCV RNA was below the detection threshold of the HCV branched- chain DNA assay than in branched-chain-DNA-positive patients. These results suggest that the HCV-specific CTL response may be able to control viral load to some extent in chronically infected patients, and they indicate that prospective studies in acutely infected patients who successfully clear HCV should be performed to more precisely define the relationship between CTL responsiveness, viral clearance, and disease severity in this infection.

Adult↗
PubMed1995

The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.

Cytotoxic T lymphocytes (CTL) are thought to contribute to viral clearance and liver cell injury during hepatitis B virus (HBV) infection. Using a strategy involving the in vitro stimulation of peripheral blood mononuclear cells (PBMC) with HBV-derived synthetic peptides containing HLA-A2.1, -A31, and -Aw68 binding motifs, we have previously described CTL responses to several epitopes within the HBV nucleocapsid and envelope antigens in patients with acute hepatitis. In this study we define six HLA-A2-restricted CTL epitopes located in the highly conserved reverse transcriptase and RNase H domains of the viral polymerase protein, and we show that the CTL response to polymerase is polyclonal, multispecific, and mediated by CD8+ T cells in patients with acute viral hepatitis, but that it is not detectable in patients with chronic HBV infection or uninfected healthy blood donors. Importantly, the peptide-activated CTL recognize target cells that express endogenously synthesized polymerase protein, suggesting that these peptides represent naturally processed viral epitopes. DNA sequence analysis of the viruses in patients who did not respond to peptide stimulation indicated that CTL nonresponsiveness was not due to infection by viral variants that differed in sequences from the synthetic peptides. CTL specific for one of the epitopes were unable to recognize several naturally occurring viral variants, except at high peptide concentration, underlining the HBV subtype specificity of this response. Furthermore, CTL responses against polymerase, core, and envelope epitopes were detectable for more than a year after complete clinical recovery and seroconversion, reflecting either the persistence of trace amounts of virus or the presence of long lived memory CTL in the absence of viral antigen. Finally, we demonstrated that wild type viral DNA and RNA can persist indefinitely, in trace quantities, in the serum and PBMC after complete clinical and serological recovery, despite a concomitant, vigorous, and sustained polyclonal CTL response. Since viral persistence is not due to escape from CTL recognition under these conditions, the data suggest that HBV may retreat into immunologically privileged sites from which it can seed the circulation and reach CTL-inaccessible tissues, thereby maintaining the CTL response in apparently cured individuals and, perhaps, prolonging the liver disease in patients with chronic hepatitis.

Acute Disease↗
PubMed1995

Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection.

It has been suggested that immune selection pressure exerted by the cytotoxic T lymphocyte (CTL) response could be responsible for viral persistence during chronic hepatitis B virus infection. To address this question, in the current study we compared the DNA and amino acid sequences of, and the CTL responses to, multiple HLA-A2-restricted CTL epitopes in the hepatitis B virus in several HLA-A2-positive patients with acute and chronic hepatitis. Our results indicate that the CTL response to these epitopes is barely detectable in the majority of patients with chronic hepatitis. Further, we show that the weak CTL response is not secondary in infection by mutant viruses lacking these epitopes, and we show that the CTL response did not select for escape mutants in any of these patients. We conclude that an ineffective hepatitis B virus specific CTL response is the primary determinant of viral persistence in chronic hepatitis and that immune selection of viral variants is not a common event in the majority of patients.

Acute Disease↗
PubMed1994

Gastroenterologic manifestations of mastocytosis.

Mastocytosis as a rare disease is usually diagnosed by dermatologists because of urticaria pigmentosa as one of the leading signs. If the triad of urticaria pigmentosa, flush and diarrhea is present diagnosis is easily made. However, urticaria pigmentosa and flush may be less dominant or even absent and gastrointestinal signs may render diagnosis more difficult. Therefore, this review is thought to describe clinical manifestations of mastocytosis from the gastroenterologist's point of view. In addition, on the grounds of a recent classification of mastocytosis practical diagnostic procedures as well as therapeutic approaches are discussed.

Acute-Phase Proteins↗
PubMed1994

GOR-antibodies in patients with chronic liver disease and hepatocellular carcinoma.

HCV infection frequently leads to liver cirrhosis and the development of hepatocellular carcinoma, while the mechanisms of carcinogenesis are still unclear. Autoantibodies like antinuclear antibodies have been described to increase and change their specificity in patients with hepatocellular carcinoma. Autoantibodies against GOR, an antigen not encoded by the viral but by the host's genome and overexpressed in tumor cells, are frequently associated with hepatitis C infection, but their significance during the development of hepatocellular carcinoma has not been determined yet. We analysed the frequency of GOR-antibodies in 38 patients with hepatocellular carcinoma on the grounds of liver cirrhosis of different origin, 38 patients with extrahepatic tumors, 24 patients with hepatitis C infection and 30 healthy controls. GOR-antibodies were found to be specifically associated with hepatitis C and were only found in patients with hepatocellular carcinoma if the liver cirrhosis was due to HCV-infection. Patients with extrahepatic tumors with or without liver metastasis had no detectable GOR antibodies, if no HCV infection was present. The determination of antibodies to the autoantigen GOR therefore has no clinical significance in patients with hepatic or extrahepatic tumors not related to HCV infection.

Adolescent↗
PubMed1989

Activation signals in human lymphocytes. Incorporation of polyunsaturated fatty acids into plasma membrane phospholipids regulates IL-2 synthesis via sustained activation of protein kinase C.

Human PBL activated with anti-TCR/CD3 mAb express high affinity receptors for IL-2, synthesize IL-2, and subsequently proliferate. In contrast, lymphocytes activated by dioctanoylglycerol (DiC8) and ionomycin express high affinity receptors; however, no IL-2 synthesis is detectable. Anti-TCR/CD3 antibodies, as well as DiC8 cause translocation of protein kinase C (PKC) from the cytosol to the plasma membrane. In DiC8-stimulated cells translocation of PKC is detectable after 15 min, then it declines to control levels. In lymphocytes activated by antiTCR/CD3 mAb translocation of PKC is detectable after 15 min, then it declines to control levels, followed by a second, long lasting activation of the enzyme up to 4 h. Addition of polyunsaturated fatty acids to DiC8 + ionomycin-treated cells leads to IL-2 synthesis and proliferation. Incorporation of poly-unsaturated fatty acids into plasma membrane phospholipids results in long term activation of PKC. The results suggest that elevated incorporation of polyunsaturated fatty acids and thus continuous activation and translocation of PKC represents a necessary early signal for IL-2 synthesis and proliferation in human lymphocytes.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗