Intragraft localization of activated nuclear factor κB in recurrent hepatitis C virus disease following liver transplantation

Nuclear factor κB (NF-κB) is activated during viral infection and is central to the regulation of host immune responses. The NF-κB activation status and its morphological sources were assessed by immunohistochemistry in allograft biopsy specimens of orthotopic liver transplantation patients with recurrent hepatitis C virus (HCV). Hepatocellular NF-κB immunostaining was detected in HCV cases compared with controls (nontransplant: P < .001; transplant: P = .006), which correlated with the number of NF-κB positive hepatocytes (P = .007) and contrasted to the absent to weak staining of controls (nontransplant: P = .001; transplant: P = .009). Enhanced NF-κB staining of cytokeratin 19-positive bile ducts and proliferating ductules in the HCV group was in contrast to controls. Intense NF-κB immunoreactivity was detected in CD68-positive Kupffer cells and macrophages of all HCV specimens compared with a few controls (nontransplant: P < .001; transplant: P = .001) and contrasted to the weak staining of controls (nontransplant: P < .001; transplant: P = .001). NF-κB-positive immunoreactivity correlated with the number of T cell receptor (TCR) α/β-positive lymphocytes (P < .001), which was not observed in controls. In those HCV cases showing evidence of necroinflammatory activity (grade) and individual features of portal inflammation, periportal inflammation/piecemeal necrosis, lobular inflammation, and fibrosis (stage), higher NF-κB staining intensity scores within bile ducts, proliferating ductules, hepatocytes (piecemeal necrosis: P = .016; stage: P = .030), and lymphocytes (stage: P = .044) and increased number of NF-κB-positive cells within bile ducts, proliferating ductules (grade, lobular inflammation, piecemeal necrosis, stage: P = .022), hepatocytes, and lymphocytes were observed. Increased staining intensity and frequency of NF-κB-positive cells were similarly observed in HCV-positive allografts obtained from patients under tacrolimus-compared with cyclosporine-based immunosuppression. These data implicate an immunoregulatory role of intragraft NF-κB activation in the pathogenesis and progression of posttransplantation HCV disease recurrence.