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Axel Ulsenheimer

Publications and source records attributed to Axel Ulsenheimer.

10 recordsLinked to original sources
PubMed2005

Uptake and presentation of hepatitis C virus-like particles by human dendritic cells.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Interaction of dendritic cells (DCs) with viral particles may play an important role in the immunopathogenesis of HCV infection. Since the synthesis or purification of infectious virions is limited, we used HCV-like particles (HCV-LPs) to study the interaction of HCV with human DCs. Immature DCs exhibited an envelope-specific and saturable binding of HCV-LPs, indicating receptor-mediated DC-HCV-LP interaction. Confocal microscopy revealed that HCV-LPs were rapidly taken up by DCs in a temperature-dependent manner. Competition experiments demonstrated that C-type lectins such as mannose receptor or DC-SIGN (DC-specific intercellular adhesion molecule 3-grabbing nonintegrin) were not sufficient for mediating HCV-LP binding. HCV-LP uptake was followed by DC activation. DCs pulsed with HCV-LPs stimulated HCV core-specific CD4(+) T cells, indicating that uptake of HCV-LPs by DCs leads to antigen processing and presentation on major histocompatibility complex (MHC) class II molecules. Finally, HCV-LP-derived antigens were efficiently cross-presented to HCV core-specific CD8(+) T cells. These findings demonstrate that HCV-LPs represent a novel model system to study HCV-DC interaction allowing definition of the molecular mechanisms of HCV uptake, DC activation, and antigen presentation to T cells. Furthermore, HCV-LP-mediated DC activation and efficient antigen presentation may explain the marked immunogenicity of HCV-LPs in vivo.

Antigen Presentation↗
PubMed2005

Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection.

Chronic evolution of acute hepatitis C (aHC) occurs in more than 80% of patients but can frequently be prevented by early treatment with interferon (IFN)-alpha. Plasmacytoid dendritic cells (pDCs) are the major endogenous IFN-alpha producers, but their role in aHC is unknown. In this study, frequency, phenotype, and pDC function were analyzed in 13 patients with aHC and 32 patients with chronic hepatitis C (cHC) compared with 20 healthy controls, 33 sustained responders to antiviral treatment, 14 patients with acute hepatitis B (aHB), and 21 patients with nonviral inflammatory disease. In aHC, pDCs in the peripheral blood were significantly reduced compared with healthy controls (median, 0.1% vs. 0.36%, P < .0005) and were inversely correlated to alanine aminotransferase levels (r = -0.823; P < .005). Circulating pDCs in aHC were immature, as determined via reduced expression of HLA-DR and CCR7, and produced little amounts of IFN-alpha (median, 3.5 pg/50,000 peripheral blood mononuclear cells [PBMCs] vs. 498.4 pg/50,000 PBMCs in healthy controls; P < .0005). Less pronounced changes were present in cHC (median, 0.17%, 28.0 pg/50,000 PBMCs IFN-alpha, respectively). However, a significantly reduced frequency and IFN-alpha production was also found in self-limited aHB (median 0.1%, 8.6 pg/50,000 PBMCs) and in patients with nonviral inflammatory disease (median 0.19%, 7.5 pg/50,000 PBMCs). In conclusion, in aHC frequency and IFN-alpha-producing capacity of peripheral blood pDCs are dramatically reduced and inversely correlated with the degree of liver inflammation. In cHC there is incomplete recovery of pDC function, which, however, could be solely due to the chronic inflammatory state.

Acute Disease↗
PubMed2005

Leucocytapheresis with Adacolumn enhances HCV-specific proliferative responses in patients infected with hepatitis C virus genotype 1.

The most important aim in controlling virus infections is to destroy infected cells. Impaired cellular immunity in HIV and HCV infection leads to chronic infection. This study examined the effect of cytapheresis on the subsequent response to interferon/ribavirin treatment in patients infected with HCV. Adacolumn cytapheresis was carried out once a day for 5 consecutive days in patients who relapsed or did not respond to previous peginterferon and ribavirin combination treatment (n = 14: relapsers = 3, non-responders = 11). Peginterferon and ribavirin combination treatment was started after cytapheresis. During combination treatment, the proliferative response of peripheral blood mononuclear cells to HCV proteins (core, NS3, NS4, and NS5), tetanus toxoid, and phytohemagglutinin was measured, and compared to the early virological response. After treatment by leucocytapheresis, the proliferative response of peripheral blood mononuclear cells to HCV-core and tetanus toxoid increased significantly over the baseline (P < 0.05). A marked increase in the phytohemagglutinin response was observed after peginterferon and ribavirin combination treatment was started (P < 0.01 at week 5 and P < 0.005 at week 13). There were, however, no clear changes in the proliferative response to other antigens. Among the 14 patients, 12 (85.7%) achieved an early virological response by week 13 (12 weeks after the start of combination treatment). After treatment, nine patients (64.3%) had a significant proliferative response to HCV core antigen. Among the nine patients, eight patients (88.9%) achieved early virological response. The results indicate that activation of cellular immunity by leucocytapheresis facilitates an early virological response rate in HCV patients. This new therapy may, therefore, become an additional therapeutic measure for HCV.

Adult↗
PubMed2004

Analysis of a successful HCV-specific CD8+ T cell response in patients with recurrent HCV-infection after orthotopic liver transplantation.

Virus-specific CD8+ T cells play a major role in antiviral immune defenses; their significance in the transplant setting, however, is unclear. In the present study, we asked whether hepatitis C virus (HCV)-specific CD8+ T cells were detectable in the presence of an immunosuppressive treatment and whether the HCV-specific CD8+ T cell response correlates with treatment outcome in patients who receive interferon (IFN)-alpha / ribavirin therapy after orthotopic liver transplantation (OLTx). Liver- and blood-derived T cell lines of 21 patients after OLTx were studied before, at the end of, and after antiviral treatment. Virus-specific IFN-gamma production in response to a panel of previously identified HCV-specific epitopes restricted by the human leukocyte antigen (HLA) class I molecules A2, A3, B7, B35, and B44 of structural and nonstructural HCV protein was determined by enzyme-linked immunospot (ELISPOT) assay. Before treatment, only low numbers of HCV-specific CD8+ T cells were detectable. In 6 patients with a sustained virological response, a significant, multispecific, and sustained CD8+ T cell response was detectable, which was mainly found in the peripheral blood. Nonresponders and transient responders showed undetectable, weak, or transient HCV-specific CD8+ T cell responses. (Sustained responders vs. transient and nonresponders: Wilcoxon rank-signed test; P < .01). In conclusion, our data indicate that despite immunosuppression, HCV-specific CD8+ T cells are detectable in patients with recurrent HCV infection after OLTx and that a significant, multispecific, and long-lasting HCV-specific CD8+ T cell response contributes to viral elimination.

Adult↗
PubMed2003

Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.

BACKGROUND & AIMS: Acute hepatitis C virus infection accounts for approximately 20% of cases of acute hepatitis today. The aim of this study was to define the natural course of the disease and to contribute to the development of treatment strategies for acute hepatitis C virus. METHODS: The diagnosis of acute hepatitis C virus in 60 patients was based on seroconversion to anti-hepatitis C virus antibodies or clinical and biochemical criteria and on the presence of hepatitis C virus RNA in the first serum sample. RESULTS: Fifty-one of 60 (85%) patients presented with symptomatic acute hepatitis C virus. In the natural (untreated) course of acute symptomatic hepatitis C (n = 46), spontaneous clearance was observed in 24 patients (52%), usually within 12 weeks after the onset of symptoms, whereas all asymptomatic patients (n = 9) developed chronic hepatitis C. The start of antiviral therapy (interferon-alpha with or without ribavirin) beyond 3 months after the onset of acute hepatitis induced sustained viral clearance in 80% of treated patients. CONCLUSIONS: The management of acute hepatitis C has to take into account the high rate of spontaneous viral clearance within 12 weeks after the onset of symptomatic disease. Treatment of only those patients who remain hepatitis C virus RNA positive for more than 3 months after the onset of disease led to an overall viral clearance (self-limited and treatment induced) in 91% of patients, and unnecessary treatment was avoided in those with spontaneous viral clearance. Patients with asymptomatic acute hepatitis C virus infection are unlikely to clear the infection spontaneously and should be treated as early as possible.

Acute Disease↗
PubMed2003

Antiviral treatment of recurrent hepatitis C virus (HCV) infection after liver transplantation: association of a strong, multispecific, and long-lasting CD4+ T cell response with HCV-elimination.

BACKGROUND/AIMS: Patients with recurrent hepatitis C virus (HCV)-infection after liver transplantation (OLTx) could develop an early, multispecific, preferentially intrahepatic CD4+ T cell response. We asked now whether there is a correlation between the HCV-specific CD4+ T cell response and treatment outcome in patients who receive interferon (IFN)-alpha/ribavirin. METHODS: Liver- and blood-derived T cell lines of 20 patients were studied in parallel before, under, at the end and after antiviral treatment. Virus-specific IFN-gamma production at a single cell level to HCV-proteins (core, non-structural protein (NS)3/4, NS5) was determined by enzyme-linked immunospot assay. RESULTS: In 6/7 non-responders a weak HCV-specific CD4+ T cell response was detectable. All six sustained responders developed a strong, at NS3/4 and NS5 directed and long-lasting CD4+ T cell response which was mainly detected in peripheral blood mononuclear cells. This reaction was significantly stronger: (1) in the responders than in the non-responders; and (2) within the responders at the end of treatment than before (P<0.03). Seven transient-responders showed a weak and/or transient HCV-specific CD4+ T cell response. CONCLUSIONS: In patients with recurrent HCV-infection after OLTx, who receive antiviral treatment, a strong, at NS3/4 and NS5 directed and long-lasting CD4+ T cell response is associated with HCV-elimination whereas no or a weak/transient response is associated with treatment failure.

Antiviral Agents↗
PubMed2003

Detection of functionally altered hepatitis C virus-specific CD4 T cells in acute and chronic hepatitis C.

Chronic hepatitis C is characterized by a weak or absent hepatitis C virus (HCV)-specific CD4(+) T-cell response in terms of antigen-specific proliferation or interferon gamma (IFN-gamma) secretion. To clarify whether this is due to the absence or functional impairment of antigen-specific CD4(+) T cells we developed an assay that relies on the induced expression of the T-cell activation marker CD25 and is therefore independent from cytokine secretion or proliferation. In 10 of 20 patients with chronic hepatitis C, a significant number of antigen-specific activated CD4(+) T cells (mean 1.06%/patient; range, 0% to 5.2% of CD4(+) T cells) could be shown, whereas antigen-specific proliferation was present in only 1 of 20 patients. IFN-gamma secretion was absent in all 13 patients tested. However, significant antigen-specific interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta) secretion was present in 6 of 10 and 3 of 10 patients, respectively. In 8 patients with acute hepatitis C, irrespective of disease outcome, HCV-specific CD4(+) T cells were detected in all patients and at a significantly higher frequency (mean 3.7%/patient; range, 1.16% to 7.17%) in the first weeks of disease. A chronic course of disease was associated either with a loss of both IFN-gamma secretion and proliferation, resembling an anergic state, or a loss of T-cell proliferation followed by a rapid decline in IFN-gamma-producing cells, corresponding to exhaustion of the specific immune response. In conclusion, functional changes of HCV-specific CD4(+) T cells or failure to develop a long-lasting T-helper response may contribute to chronic hepatitis C viral persistence.

Acute Disease↗
PubMed2003

Upregulation of major histocompatibility complex class I on liver cells by hepatitis C virus core protein via p53 and TAP1 impairs natural killer cell cytotoxicity.

The mechanisms of immune evasion and the role of the early immune response in chronic infection caused by hepatitis C virus (HCV) are still unclear. Here, we present evidence for a cascade of molecular events that the virus initiates to subvert the innate immune attack. The HCV core protein induced p53-dependent gene expression of TAP1 (transporter associated with antigen processing 1) and consecutive major histocompatibility complex (MHC) class I upregulation. Moreover, in p53-deficient liver cell lines, only reconstitution with wild-type p53, but not mutated p53 lacking DNA binding capacity, showed this effect. As a consequence of increased MHC class I expression, a significantly downregulated cytotoxic activity of natural killer (NK) cells against HCV core-transfected liver cells was observed, whereas lysis by HCV-specific cytotoxic T cells was not affected. These results demonstrate a way in which HCV avoids recognition by NK cells that may contribute to the establishment of a chronic infection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Hepatitis C virus eradication associated with hepatitis B virus superinfection and development of a hepatitis B virus specific T cell response.

BACKGROUND/AIMS: Specific T cell responses during acute hepatitis B and during chronic hepatitis C have been described in detail. However, the T cell responses during the rare setting of acute hepatitis B virus (HBV) infection in the course of chronic hepatitis C that eventually lead to clearance of both viruses are completely unknown. METHODS: We analyzed the virus specific CD4+ and CD8+ T cell response during an acute HBV superinfection in a patient with chronic hepatitis C. RESULTS: The patient eliminated hepatitis C virus (HCV)-RNA and HBV-DNA from serum soon after the clinical onset of acute hepatitis B. The HBV specific T cell response found in this patient corresponds to the typical response that has been described in acute hepatitis B without chronic HCV infection. In contrast the hepatitis C specific immune response was similar to that generally found in chronic hepatitis C despite the fact that the patient also eliminated HCV-RNA. CONCLUSIONS: We hypothesize that the acute HBV infection induced a HBV specific T cell response which was associated with elimination HBV DNA and HCV-RNA, the latter possibly by bystander mechanisms, e.g. via secretion of cytokines. If such a non-specific bystander mechanism which has proven to be effective in the experimental setting and which is formally described here for a single patient can be shown to be a more general phenomenon, it may support the approach with new antiviral strategies, e.g. the induction of non-specific defense mechanisms against HCV.

Acute Disease↗