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- Materials and Methods
- Transparency Declaration
The understanding of successful virus elimination mediated by the immune response to hepatitis C virus (HCV) infection is far from settled. Both viral and host factors are determinants for the spontaneous elimination or persistence of the virus. In HCV infection, some 50–90% of the patients develop chronic disease . There is evidence that unspecific CD8 cells and a subset of antigen-specific CD4 cells deviating T-helper cells in a TH1 profile (interferon (IFN) and tumour necrosis factor-α) play a pivotal role in the immune response to the HCV .
A rapid and strong host T cell response plays a major role in effective clearance of the HCV virus. Most likely, the tendency towards chronic infection represents a lack of a strong and specific immune response to viral antigens as well as an ineffective rapid clearance of the HCV [3,4].
The recruitment of effector cells from the blood stream to the liver is dependent upon local chemokines and their receptors. Chemokines constitute a large family of small proteins consisting of four main subfamilies (CXC, CC, C, CX3C) mediating their effects on a family of seven-transmembrane domain G-protein coupled receptors . The chemokines are responsible for the leukocyte migration by creating a chemical gradient from the vascular endothelium to the infected cells  and by selective expressions of different chemokine receptors on the leukocytes .
There is increasing evidence for a role of chemokines as inflammatory mediators in HCV infection .
The CC chemokines macrophage inflammatory protein (MIP)-1α (CCL3), MIP-1β (CCL4) and the regulated on activation, normal T expressed and secreted (RANTES) chemokine (CCL5) are expressed by the portal vessel endothelium and recruit macrophages and lymphocytes into the liver [6,9]. These chemokines bind to their corresponding receptors, CCR5, on lymphocytes with type 1 cytokine secretion [9,10]. Theoretically, both the chemokine response to HCV and the availability of the corresponding receptors on the lymphocytes are obligatory for a strong immunological response to the virus. Genetically determined loss of CCR5 expression has been linked to chronic hepatitis . Most studies, although not all, have shown increased intrahepatic and/or blood levels, as well as increased expression, of the CXC and CC families of chemokines in chronic HCV infection . However, the exact role of chemokines both in spontaneous remission and in response to immunomodulatory agents such as IFN-α is so far poorly understood. According to the few studies available, high baseline serum levels of MIP-3α  are associated with a positive prognostic response, whereas high levels of IFN-γ-inducible protein 10 are associated with a negative prognostic response to treatment [13,14]. Moreover, increase in CXCR3-expressing CD8+ cells during treatment has been associated with achievement of virus control . However, the dynamics of the apparent critical initial rapid CC chemokine response with emphasis on clearance of virus is so far not well investigated.
Therefore, in the present study, we describe the blood concentrations of MIP-α, MIP-β, monocyte chemoattractant protein (MCP)-1 and RANTES and their relationship to liver enzyme levels, microbiological and histological parameters at baseline, and then describe the association between the initial (24 h) chemokine response and the final clinical outcome of the treatment of chronic HCV infection.
- Top of page
- Materials and Methods
- Transparency Declaration
In the present study, we have shown that baseline serum levels of the CC chemokines MIP-1α, MIP-1β, MCP-1 and RANTES were increased compared to healthy controls. There were no significant relationships between the serum levels of the chemokines and liver function tests, microbiological and histological parameters. Of the various chemokines studied, a rapid (24 h) response exclusively associated with a sustained virological response (SVR) was observed only for MIP-1α, MIP-1β and RANTES. MCP-1 was increased in both the SVR and non-SVR group, although no differences between the two responder groups were observed.
In agreement with several previous studies, the serum levels of CC chemokines were increased in patients with chronic HCV infection compared to healthy controls . Increased intrahepatic expression has also been reported for CC chemokines [17,18]. Furthermore, in the present study, serum levels of the CC chemokines were not associated with the grade of necroinflammatory activity or the fibrosis grade. In the literature, there are conflicting results concerning this topic; in one study, serum MIP-3α and ALT correlated significantly ; in another study, intrahepatic RANTES expression correlated well with the histological activity , whereas, in yet another study, the expression of RANTES or MIP-1β in the liver did not correlate with necroinflammation activity scores . Most likely, during a chronic HCV infection, there is an inflammatory circle: an activated chemokine response is responsible for recruitment of inflammatory cells, which in turn activate further production of cytokines and chemokines. This inflammatory circle is in turn responsible for the chronic necroinflammation and the development of cirrhosis . However, the exact contribution of chemokines and especially the CC chemokines to this inflammatory circle is unclear and needs further studies.
The conventional treatment of chronic HCV infection consists of a combination of the immunomodulatory and antiviral agents IFN-α and ribavirin. Several studies have shown that a rapid viral clearance from the general circulation is associated with a high rate of sustained virological response . It has been proposed that the natural immune response to the HCV has to be rapid, strong and complete with the various epitopes to prevent virus escape and subsequent chronic inflammation . Therefore, the present study was designed to study early (24 h) responses of the CC chemokines during the initiation of antiviral treatment. Significant increases exclusively associated with a sustained virological response were observed for MIP-1α and MIP-1β. For RANTES, the responses at 24 h were less pronounced but were at significant levels between the two groups.
It is of interest to note that MCP-1 levels were also increased at 24 h of treatment in the sustained response group and in the relapser group, but not in the nonresponder group. Our data indicate that, of the various chemokines mediating the immune response during the treatment, MIP-1α, MIP-1β and RANTES, in contrast to MCP-1, apparently play an important role in inducing an effective clearance of the HCV.
Interestingly, the present data indicate a possible role of early chemokine response as a predictor of an SVR response. As can be seen form the ROC curves in Fig. 2, the assays cannot yield both high sensitivity and specificity at the same time because this would require a steep sigmoid curve shape with an area approaching 1. The clinical use of such a test would be to decide whether a patient should discontinue treatment, assuming the patient will not respond to treatment. Consequently, the cut-off values were set for high sensitivity of response to give the patient the benefit of doubt.
The present study indicates that various chemokines play a role in mediating an effective immunomodulatory role during treatment of HCV infection. However, the results obtained must be interpretated with great caution. First, the number of patients studied was low and two types of treatment with IFN-α were used in the patients studied. Second, the study was not primarily designed to test independent 24-h chemokine responses to the final clinical outcome. A future study should be prospective and properly stratified for potential confounding factors such as sex, genotypes and grade of liver cirrhosis. In this setting, a possible role of early chemokine response as a clinical predictor of sustained virological response could be better evaluated.
In conclusion, serum levels of CC chemokines are elevated in chronic HCV infection but not associated with the grade of necroinflammation. An early response of MIP-1α, MIP-1β and RANTES to treatment may predict an effective HCV clearance.