Reconstitution of hepatitis C virus-specific T-cell-mediated immunity after liver transplantation

Abstract

Hepatitis C virus (HCV)-related liver failure is the leading indication for liver transplantation worldwide. After transplantation, virological recurrence is the rule, but the spectrum of histological injury is wide, ranging from the development of allograft cirrhosis within a few years to minimal hepatitis despite long-term follow-up. The immunological correlates of this variable natural history are poorly understood. Here, we studied the kinetics of the cellular immune responses, viral replication, and allograft histology in 24 patients who had undergone liver transplantation for HCV-related liver failure. Using direct ex vivo methodologies (i.e., interferon-gamma ELISPOT and major histocompatibility complex class I-peptide tetrameric complexes), we found that patients who experienced viral eradication after antiviral therapy showed restoration of HCV-specific T-cell responses, whereas patients with progressive HCV recurrence that failed to respond to therapy showed declining frequencies of these viral-specific effector cells. The cytotoxic T lymphocytes that peripherally reconstituted after transplantation were clonotypically identical to those present within the recipient explant liver, defined at the level of the T-cell receptor beta chain (one epitope/one clone). Moreover, the subset of patients who spontaneously demonstrated minimal histologic recurrence had more vigorous CD4 ؉ T-cell responses in the first 3 months, particularly targeting nonstructural proteins. We provide evidence that T-cell responses emerge after liver transplantation, and their presence correlates with improved histological and clinical outcomes. In conclusion, these results may help identify patients more likely to develop severe HCV recurrence and therefore benefit from current antiviral therapy, as well as provide a rationale for the future use of novel immunotherapeutic approaches. H epatitis C virus (HCV) infection is characterized by the high likelihood of chronicity after acute infection and significant risk of disease progression to cirrhosis and liver failure. Immune responses appear to be crucial in the control of infection, and patients with self-limited courses of acute HCV demonstrate coordinated activation of viral-specific CD4 ϩ and CD8 ϩ T cells that produce type 1 cytokines such as interferon gamma (IFN-␥) and tumor necrosis factor-␣. 1 Moreover, these T-cell responses can be maintained for decades after recovery. Cellular immune responses also may offer varying degrees of protection against viral replication and tissue damage in persistent infection. 2 For example, an inverse correlation between levels of HCV-specific cytotoxic T lymphocytes, and viral load has been observed in humans and chimpanzees, 3-5 and HCV-related pathology is more prevalent in the setting of human immunodeficiency virus immune suppression. 2 HCV-related liver failure is the single most common indication for orthotopic liver transplantation (OLT) worldwide. 6 Recurrent HCV infection, as defined by viremia after transplantation, is nearly univ...

Selective decrease in hepatitis C virus-specific immunity among African Americans and outcome of antiviral therapy

“…16 We coated a total of 96-well nitrocellulose-backed plates (MAHA S4510; Millipore, Bedford, MA) as recommended by the manufacturer with 10 g/mL capture mouse anti-IFN-␥ (1-D1K; Mabtech AB, Nacka, Sweden) overnight at room temperature. We then washed plates 3 times with PBS/0.05% Tween 20 (Sigma), and blocked them with RPMI/10% human serum for 1 hour at room temperature.…”

Sustained resolution of fibrosing cholestatic hepatitis C despite viremic relapse after stopping pegylated interferon and ribavirin therapy

“…Reconstitution of CD8ϩ T-cell responses to HCV antigens has been described in FCH cases after response to antiviral therapy. 2 Such reconstitution is not seen in patients unresponsive to treatment. Antiviral therapy leading to control of viral load and cytopathic damage probably allowed time for immune reconstitution.…”

Evolution of the NS3 and NS5B Regions of the Hepatitis C Virus During Disease Recurrence After Liver Transplantation

“…Patients with mild recurrence presented higher intersample GD and, a trend towards a greater number of Aa fixations, as compared with patients undergoing severe recurrence. Although multiple variables (such as host-related factors and the genetic back-ground of the graft) may influence the severity of the recurrence, previous studies have shown that severe hepatitis recurrence after LT occurred in patients with impaired HCV-specific T-cell responses, whereas the histological and clinical outcomes were better in those with efficient T-cell response (42,43). Therefore, the increased degree of genetic diversification of the NS5b region in patients with mild recurrence might be a consequence of a more prominent immunological pressure in this group of patients.…”