No abstract

No abstract

The hepatitis C virus (HCV)-specific CD8؉ -T-cell response is thought to play a critical role in HCV infection. Studies of these responses have largely relied on the analysis of a small number of previously described or predicted HCV epitopes, mostly restricted by HLA A2. In order to determine the actual breadth and magnitude of CD8؉ -T-cell responses in the context of diverse HLA class I alleles, we performed a comprehensive analysis of responses to all expressed HCV proteins. By using a panel of 301 overlapping peptides, we analyzed peripheral blood mononuclear cells (PBMC) from a cohort of 14 anti-HCV-positive, HLA A2-positive individuals in an enzyme-linked immunospot assay. Only four subjects had detectable HLA A2-restricted responses in PBMC, and only 3 of 19 predicted A2 epitopes were targeted, all of which were confirmed by tetramer analysis. In contrast, 9 of 14 persons showed responses with more comprehensive analyses, with many responses directed against previously unreported epitopes. These results indicate that circulating HCV-specific CD8؉ -T-cell responses can be detected in PBMC in the majority of infected persons and that these responses are heterogeneous with no immunodominant epitopes consistently recognized. Since responses to epitopes restricted by single HLA alleles such as HLA A2 do not predict the overall response in an individual, more comprehensive approaches, as shown here, should facilitate definition of the role of the CD8 ؉ -T-cell response in HCV infection. Moreover, the low level or absence of responses to many predicted epitopes provides a rationale for immunotherapeutic interventions to broaden cytotoxic-T-lymphocyte recognition. The CD8ϩ T-cell response is thought to play a crucial role in the course of hepatitis C virus (HCV) infection. In humans and in chimpanzees, a strong and broadly directed HCV-specific cytoxoxic-T-lymphocyte (CTL) response has been associated with viral clearance during acute HCV infection (7,29). In contrast, individuals with chronic infection are often found to have a relatively weak and narrowly directed CD8 ϩ -T-cell response against HCV (reviewed in reference 27). Whether these responses in chronic disease are still beneficial in containing viral replication or whether they are mediators of hepatic injury and disease is unclear. In several studies, the magnitude of the HCV-specific CD8 ϩ -T-cell response has been correlated to HCV viral load and to liver histology, but the results of these studies have been mixed (17,31,33,34,41). Overall, the levels of responses detected by most investigators, using a variety of methods, have been fairly low compared to those found in many other viral infections.Thus far, most studies of the HCV-specific CD8 ϩ -T-cell response have been undertaken in HLA A2-positive individuals, and the analysis usually has been restricted to a set of previously described HLA A2-restricted HCV epitopes or to HCV peptides shown to bind strongly to HLA A2 and therefore predicted to elicit responses (2,4,5,14,15,28,30,33,34,(37)(38)(3...

Our results suggest that CE may be of clinical value in selected patients with FAP, whereas in PJS, CE could be used as first line surveillance procedure.

Hepatic cirrhosis is a life-threatening disease arising from different chronic liver disorders. One major cause for hepatic cirrhosis is chronic hepatitis C. Chronic hepatitis C is characterized by a highly variable clinical course, with at least 20% developing liver cirrhosis within 40 years. Only liver biopsy allows a reliable evaluation of the course of hepatitis C by grading inflammation and staging fibrosis, and thus serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed. To identify new candidate biomarkers for hepatic fibrosis, we performed a proteomic approach of microdissected cirrhotic septa and liver parenchyma cells. In cirrhotic septa, we detected an increasing expression of cell structure associated proteins, including actin, prolyl 4-hydroxylase, tropomyosin, calponin, transgelin, and human microfibril-associated protein 4 (MFAP-4).

No abstract

Multispecific CD8؉ T-cell responses are thought to be important for the control of acute hepatitis C virus (HCV) infection, but to date little information is actually available on the breadth of responses at early time points. Additionally, the influence of early therapy on these responses and their relationships to outcome are controversial. To investigate this issue, we performed comprehensive analysis of the breadth and frequencies of virus-specific CD8؉ T-cell responses on the single epitope level in eight acutely infected individuals who were all started on early therapy. During the acute phase, responses against up to five peptides were identified. During therapy, CD8؉ T-cell responses decreased rather than increased as virus was controlled, and no new specificities emerged. A sustained virological response following completion of treatment was independent of CD8 ؉ T-cell responses, as well as CD4 ؉ T-cell responses. Rapid recrudescence also occurred despite broad CD8 ؉ T-cell responses. Importantly, in vivo suppression of CD3 ؉ T cells using OKT3 in one subject did not result in recurrence of viremia. These data suggest that broad CD8 ؉ T-cell responses alone may be insufficient to contain HCV replication, and also that early therapy is effective independent of such responses.

No abstract