Sustained and focused hepatitis B virus nucleocapsid–specific T-cell immunity in liver transplant recipients compared to individuals with chronic and self-limited hepatitis B virus infection

Abstract

Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) is associated with poor graft-and patientsurvival. Treatment with HBV-specific immunoglobulins (HBIG) in combination with nucleos(t)ide analogs is effective in preventing HBV reinfection of the graft and improving OLT outcome. However, the role of HBV-specific cellular immunity in viral containment in immune suppressed patients in general and in OLT recipients in particular is unclear. To test whether or not OLT recipients maintain robust HBV-specific cellular immunity, the cellular immune response against HBV was assessed in 15 OLT recipients and 27 individuals with chronic and 24 subjects with self-limited HBV infection, respectively; using an overlapping peptide set spanning the viral nucleocapsid-and envelope-protein sequences. The data demonstrate that OLT recipients mounted fewer but stronger clusters of differentiation (CD)8 T cell responses than subjects with self-limited HBV infection and showed a preferential targeting of the nucleocapsid antigen. This focused response pattern was similar to responses seen in chronically infected subjects with undetectable viremia, but significantly different from patients who presented with elevated HBV viremia and who mounted mainly immune responses against the envelope protein. In conclusion, virus-specific CD4 T cell-mediated responses were only detected in subjects with self-limited HBV infection. Thus, the profile of the cellular immunity against HBV was in immune suppressed patients similar to subjects with chronic HBV infection with suppressed HBV-DNA. Liver Transpl 14:478-485, 2008. © 2008 AASLD. Received July 4, 2007 accepted October 6, 2007. Five to ten percent of all orthotopic liver transplantations (OLTs) for end-stage liver disease are related to hepatitis B virus (HBV) infection. 1,2 Recurrent HBV infection after OLT is a major complication, frequently leading to graft failure or patient death. 3 Without prophylaxis, the risk of graft reinfection is about 80%,

Hepatitis B virus cellular immunity after liver transplantation: A role in preventing hepatitis B virus recurrence?

“…In contrast with reports in nontransplanted patients showing that antiviral‐induced control of the viral load results in transient restoration of HBV immunity,16 this increase has not been observed in patients with negative viremia after LT 20, 21. On the contrary, as reported by Luo et al,19 in patients with HBV recurrence after LT, the magnitude of T cell responses appears to be antigen‐driven and deleterious because T cell proliferative and secreting responses correlate to the viral load and alanine aminotransferase levels.…”

“…Interestingly, in the study by Luo et al,19 not all LT recipients with suppressed HBV replication showed an undetectable T cell response; a few of them had anti‐HBc reactivity similar to that of patients with resolved HBV infection. By studying a smaller number of LT patients with successful HBIG prophylaxis, Bihl et al21 recently provided evidence of a focused T cell response to HBc. By using a set of overlapping peptides in an interferon gamma enzyme‐linked immunosorbent spot assay (ELISPOT), they showed a narrow response to HBc peptides in LT patients but with a magnitude significantly higher than that in viremic patients and in patients with resolved infection and similar to that of chronically infected subjects with low viremia.…”

Anti-HBs re-seroconversion after liver transplantation in a patient with past HBV infection receiving a HBsAg positive graft

“…HBsAg and HBV DNA were undetectable and anti-HBs very high the first three Table 1 Amino acid sequence and protein location of peptides targeted by the OLT recipient. A set of 208 overlapping peptides (OLP) was synthesized covering the entire HBV proteome including the nucleocapsid protein (24 peptides), envelope (53 OLP), X-protein (20 OLP) and polymerase protein (111 OLP) as described [13]. Peptides were adapted 18-mers overlapping by 10 amino acids and were based on the reported HBV genotype D reference strain ayw since HBV genotype D is predominant in Italy.…”

“…Peripheral blood mononuclear cells (PBMC) were isolated as described [13], stimulated as outlined below and used in an interferon gamma (IFN c) based enzyme-linked immunospot (ELISpot) assay at 100,000 PBMC/well. ELISpot assays for all time points were performed at the same time and peptides were tested in 59 peptide matrix pools as described previously [15].…”

“…HBV-specific cellular and humoral immunity plays a key role in the course and outcome of HBV infection in immunocompetent patients [12]. Recent analyses of the HBV-specific cellular immunity in OLT recipients have shown a profile similar to that of patients with chronic HBV infection and suppressed HBV-DNA, with a preferential targeting to the viral nucleocapsid antigen [13]. These data indicate that transplanted subjects can maintain or even develop new virus-specific cellular immunity, contributing to viral control after transplantation [13].…”