1 Department of Medicine II, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, D-81377 Munich, Germany; 2 Institute for Immunology, University of Munich, Goethestrasse 31, D-80336 Munich, Germany
Received 19 February 2004; returned 26 March 2004; revised 2 April 2004; accepted 23 April 2004
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Abstract |
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Keywords: T cells , ELISpot assay , interferon , ribavirin , antiviral therapy
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Introduction |
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Natural history of recurrent HCV infection following OLTx |
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Taking all risk factors into account, immune status appears to be the main variable influencing disease progression in recurrent HCV infection.15,16 Risk factors for aggressive recurrence, graft loss, and death are methylprednisolone pulse therapy, treated acute cellular rejection, cytomegalovirus (CMV) infection and use of OKT3.1719 However, the benefit of steroid withdrawal, although commonly practised in transplant recipients with hepatitis C, has not been proved.20
There appears to be no consistent difference between cyclosporin and tacrolimus in their effects on hepatitis C.10 Mycophenolate mofetil may show synergic antiviral properties when used with interferon; however, post-transplantation use has not been associated with consistent beneficial or deleterious effects.21 Global immunosuppression level, not a single immunosuppressive agent, dominates the effect on recurrence of HCV; the management of immunosuppression is therefore controversial and further clinical studies are required.
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Antiviral treatment of recurrent HCV infection following OLTx |
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There are scant data concerning the optimal timing of the antiviral therapy; a prospective trial directly comparing antiviral therapy initiated prophylactically compared with initiation at histological recurrence has not been performed. From the studies available there is no compelling evidence that the immunostimulatory effects of interferon- induce acute cellular rejection or are associated with a significantly increased frequency or severity of rejection in liver transplant recipients.22,2426 Optimal timing and duration of treatment still have to be defined in further trials. Future therapeutic approaches may include molecular therapies that directly inhibit HCV protein processing and RNA replication. This may allow safe and effective pre-transplantation suppression and post-transplantation prophylaxis.
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Retransplantation |
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Cellular immune response in patients with recurrent HCV infection after OLTx |
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The mechanisms of viral control in HCV infection are poorly understood. There are several lines of direct and indirect evidence that suggest that deficient cell-mediated immunity plays a key role in the development of chronic HCV infection. Vigorous and multispecific T cell responses associated with viral clearance in acute hepatitis C have been found by several groups whereas in chronic infection T cell responses are attenuated and difficult to detect ex vivo.3032 In the transplant setting treatment with OKT3 or coinfection with CMV, which has been shown to induce cell-mediated immune defects, has been associated with a higher risk of HCV-related allograft cirrhosis.18,19
Up to now only very few studies have investigated the role of the specific cellular immune responses in the pathogenesis of HCV-induced allograft injury. Concerning the CD8+ T cell response no studies are available. Among other things, e.g. HLA class I mismatch, this is due to the fact that there are several technical limitations concerning the analysis of HCV-specific CD8+ T cells. In contrast the CD4+ T cell response has been studied by Rosen et al. and our group.
In one of our studies we analysed liver- and blood-derived T cell lines of 34 patients with recurrent HCV infection. Virus-specific interferon- production in response to various HCV proteins (structural as well as non-structural parts of the virus) was determined by ELISpot assay. As antigens we used the structural core protein (amino acids 1120) and the non-structural (NS)3/4 (amino acids 11921931) and NS5 (amino acids 20143010) proteins. In up to 60% of these patients we found an HCV-specific CD4+ T cell response characterized by production of
-interferon. The HCV-specific CD4+ T cell response was preferentially localized on liver as opposed to peripheral blood cells. HCV-specific CD4+ T cells were more often detected early (
6 months) than late (>6 months) after OLTx. During the early phase after OLTx NS3/4 was more often recognized than structural protein core or NS5. This is reminiscent of patients with acute self-limited hepatitis C infection whose multispecific CD4+ T cell response is also mainly directed at NS protein; however, the HCV-specific T cell response in the transplant setting seems to be less efficient, compared with patients with acute hepatitis C infection who spontaneously clear the virus and have a self-limited disease in up to 50% of cases.33 The reasons for this observation are a matter of debate. Chimerism of dendritic cells and other immunocompetent cells as well as HLA mismatch may account for this lower efficiency or lower strength of the HCV-specific CD4+ T cell response. During the late phase after OLTx a virus-specific CD4+ T cell response was less frequently detectable and was directed equally against structural protein core and NS proteins. This is similar to the chronic course of hepatitis C.3436
Rosen et al.37 investigated the HCV-specific CD4+ T cell response in peripheral blood in patients with minimal or no histological recurrence and found a significant T cell proliferation to more than one HCV antigen in 40% of these patients; however, in patients with severe recurrence of HCV or HCV-related cirrhosis of the allograft they did not find such a response. In contrast to these observations we found no correlation between HCV-specific CD4+ T cells and histology, histological activity index (HAI), liver enzymes or viral load. The majority of our patients with rejection or non-specific histology had detectable amounts of HCV-specific CD4+ T cells.35 Different read-out systems used in the study by Rosen et al. (proliferation assay) and our group (ELISpot assay) may explain the contradictory results of the two studies. In addition we investigated liver tissue and PBMC whereas Rosen et al. focused on PBMC. CD4+ T cells able to proliferate may be unable to produce interferon-
HCV-specific CD4+ T cell response during and after antiviral therapy
More recently we showed in another study of 20 patients with recurrent infection, that despite immunosuppression, a sustained antiviral response is associated with a strong, multispecific CD4+ T cell response which is mainly directed at NS proteins. This response was maintained in PBMC over a long period, and it was significantly stronger in sustained responders than in transient responders or non-responders.
We found, with one exception, that the HCV-specific CD4+ T cell response during viral elimination was preferentially localized in the PBMC; this indicates that there is no attraction of virus-specific T cells in the liver after viral elimination.38
From the available data we conclude that the CD4+ T cell response plays an important role in viral clearance in recurrent HCV infection after OLTx.
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Conclusions |
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Acknowledgements |
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Footnotes |
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References |
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