Intrahepatic cytokine profiles associated with posttransplantation hepatitis C virus[ndash ]related liver injury

Abstract

Recurrent chronic hepatitis, cholestatic hepatitis, and acute rejection in conjunction with hepatitis C virus (HCV) recurrence are well-recognized clinical sequelae of reinfection of the hepatic allograft with HCV. The aim of this study is to characterize intrahepatic cytokine responses associated with reinfection of the allograft with HCV in these settings. Intrahepatic messenger RNA expression of T helper cell subtype 1 (TH1) cytokines interleukin-2 (IL-2), interferon-␥, and tumor necrosis factor-␣ and TH2 cytokines IL-4 and IL-10 was measured by real-time polymerase chain reaction system using TaqMan probes in 53 liver specimens from six groups of patients. These were: (1) recurrent chronic hepatitis C (CH-I; n ‫؍‬ 15), (2) cholestatic hepatitis (n ‫؍‬ 6), (3) acute rejection associated with HCV recurrence (AR-HCV; n ‫؍‬ 12), (4) acute rejection in non-HCV-infected allografts (AR non-HCV; n ‫؍‬ 5), (5) patients with chronic hepatitis C who did not undergo transplantation (CH-C; n ‫؍‬ 10), and (6) nondiseased liver tissue (n ‫؍‬ 6). Intrahepatic viral loads were measured using an Amplicor monitor assay (Roche Diagnostic Systems, Branchburg, NJ). The CH-I and CH-C groups had similar TH1 intrahepatic cytokine profiles. Compared with the CH-I group, the cholestatic group expressed increased levels of the TH2 cytokines IL-10 (P ‫؍‬ .024) and IL-4 (P ‫؍‬ .0024). The AR-HCV group also expressed more TH2 cytokines IL-10 (P ‫؍‬ .014) and IL-4 (P ‫؍‬ .034) compared with the CH-I group. Both the AR-HCV and AR non-HCV groups showed similar intrahepatic cytokine profiles. Intrahepatic viral loads were highest in the cholestatic group compared with the AR-HCV, CH-I, and CH-C groups (P ‫؍‬ .0007). In conclusion, a novel observation is that the cholestatic group showed upregulation of the TH2 cytokines IL-10 and IL-4, in addition to high viral loads. In this setting, the E nd-stage liver disease associated with hepatitis C virus (HCV) infection is now the leading indication for liver transplantation in adults. However, after transplantation, HCV invariably reinfects the liver allograft. 1-3 Reinfection of the graft is characterized by different patterns of allograft injury, including recurrent chronic hepatitis C, cholestatic hepatitis C, and acute rejection associated with HCV recurrence. Studies examining the immunopathogenesis of these varying forms of HCV-related liver allograft injury remain limited.In the nonimmunosuppressed setting, several studies have shown that liver injury occurs in the context of an immune response. [4][5][6] Moreover, studies have shown that the intrahepatic cytokine milieu tends toward a T helper cell subtype 1 (TH1) profile. [7][8][9][10] In addition, intrahepatic interferon-␥ (IFN-␥) and interleukin-2 (IL-2) messenger RNA (mRNA) levels correlated with hepatic fibrosis and portal tract inflammation. 7 However, data regarding intrahepatic cytokine profiles in different forms of HCV-related allograft injury remain scarce. In the posttransplantation setting, immunosuppression may modify the patho...

Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors

“…16 These laboratory phenomena suggest that the significant hepatocyte regeneration that occurs after LDLT may promote HCV replication. Our observation that the incidence of CHC a syndrome associated with significant serum and intrahepatic viral replication 17,18 was significantly more common in LDLT versus CAD may imply that this concept is valid. However, although these laboratory phenomenon suggest that grafts procured from living donors may be more vulnerable to HCV reinfection and histologic injury, we did not observe a significantly greater overall incidence or earlier recurrence of HCV in LDLT when compared with CAD.…”

Impact of immunosuppression on immunopathogenesis of liver damage in hepatitis C virus-infected recipients following liver transplantation

“…Similar to the nontransplantation setting, a positive correlation was seen between interferon ␥ mRNA level and degree of liver fibrosis. 17,27 Other studies have shown that more aggressive hepatitic disease posttransplantation is associated with increased levels of CD69 ϩ cells (activated lymphocytes) and increased expression of such inflammatory adhesion molecules as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 and major histocom-patibility complex molecules. 28 Increased activity of this hepatitic disease also is associated with increased liver Fas mRNA levels and increased hepatocyte apoptosis.…”

“…This syndrome is associated with much greater viral loads in both serum and liver than usually observed in chronic hepatitis. 9,15,17 Three studies also examined HCV quasispecies during this time. [18][19][20] Although these studies suggest different results, in common, they all show that during the cholestatic phase, quasispecies tend to be stable and not fluctuate, as in hepatitic disease.…”

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

“…At least 2 studies suggest that FCH patients have a T-helper 2 driven response to hepatitis C recurrence as opposed to a T-helper 1 driven response typically seen in hepatitis C recurrence. 4,5 We cannot recommend limited courses of antiviral therapy for FCH based on this one case, and our practice will continue to be long-term therapy at lowest dosages possible after response is obtained. However, our case suggests a less permanent immune defect for some patients and offers hope that FCH may not lead to rapid graft failure without long-term antiviral therapy.…”