Liver transplantation from hepatitis B surface antigen positive donors: a safe way to expand the donor pool.

BACKGROUND & AIMS: The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study. METHODS: From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42 months (range 12-60). All recipients were HBcAb positive and were given antiviral prophylaxis. RESULTS: Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection. CONCLUSIONS: OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy.

HIV patients developing primary CNS lymphoma lack EBV-specific CD4+ T cell function irrespective of absolute CD4+ T cell counts.

BACKGROUND: In chronic HIV infection, antiretroviral therapy-induced normalization of CD4(+) T cell counts (immune reconstitution [IR]) is associated with a decreased incidence of opportunistic diseases. However, some individuals remain at risk for opportunistic diseases despite prolonged normalization of CD4(+) T cell counts. Deficient Epstein-Barr virus (EBV)-specific CD4(+) T cell function may explain the occurrence of EBV-associated opportunistic malignancy-such as primary central nervous system (PCNS) lymphoma-despite recovery of absolute CD4(+) T cell counts. METHODS AND FINDINGS: Absolute CD4(+) T cell counts and EBV-specific CD4(+) T cell-dependent interferon-gamma production were assessed in six HIV-positive individuals prior to development of PCNS lymphoma ("cases"), and these values were compared with those in 16 HIV-infected matched participants with no sign of EBV-associated pathology ("matched controls") and 11 nonmatched HIV-negative blood donors. Half of the PCNS lymphoma patients fulfilled IR criteria (defined here as CD4(+) T cell counts >or=500/microl blood). EBV-specific CD4(+) T cells were assessed 0.5-4.7 y prior to diagnosis of lymphoma. In 0/6 cases versus 13/16 matched controls an EBV-specific CD4(+) T cell response was detected (p = 0.007; confidence interval for odds ratio [0-0.40]). PCNS lymphoma patients also differed with regards to this response significantly from HIV-negative blood donors (p < 0.001, confidence interval for odds ratio [0-0.14]), but there was no evidence for a difference between HIV-negative participants and the HIV-positive matched controls (p = 0.47). CONCLUSIONS: Irrespective of absolute CD4(+) T cell counts, HIV-positive patients who subsequently developed PCNS lymphoma lacked EBV-specific CD4(+) T cell function. Larger, ideally prospective studies are needed to confirm these preliminary data, and clarify the impact of pathogen-specific versus surrogate marker-based assessment of IR on clinical outcome.

Simultaneous assessment of cytotoxic T lymphocyte responses against multiple viral infections by combined usage of optimal epitope matrices, anti- CD3 mAb T-cell expansion and "RecycleSpot"

The assessment of cellular anti-viral immunity is often hampered by the limited availability of adequate samples, especially when attempting simultaneous, high-resolution determination of T cell responses against multiple viral infections. Thus, the development of assay systems, which optimize cell usage, while still allowing for the detailed determination of breadth and magnitude of virus-specific cytotoxic T lymphocyte (CTL) responses, is urgently needed. This study provides an up-to-date listing of currently known, well-defined viral CTL epitopes for HIV, EBV, CMV, HCV and HBV and describes an approach that overcomes some of the above limitations through the use of peptide matrices of optimally defined viral CTL epitopes in combination with anti-CD3 in vitro T cell expansion and re-use of cells from negative ELISpot wells. The data show that, when compared to direct ex vivo cell preparations, antigen-unspecific in vitro T cell expansion maintains the breadth of detectable T cell responses and demonstrates that harvesting cells from negative ELISpot wells for re-use in subsequent ELISpot assays (RecycleSpot), further maximized the use of available cells. Furthermore when combining T cell expansion and RecycleSpot with the use of rationally designed peptide matrices, antiviral immunity against more than 400 different CTL epitopes from five different viruses can be reproducibly assessed from samples of less than 10 milliliters of blood without compromising information on the breadth and magnitude of these responses. Together, these data support an approach that facilitates the assessment of cellular immunity against multiple viral co-infections in settings where sample availability is severely limited.

Virus-specific immune response in HBeAg-negative chronic hepatitis B: relationship with clinical profile and HBsAg serum levels.

BACKGROUND AIMS: The immune impairment characterizing chronic hepatitis B (cHBV) infection is thought to be the consequence of persistent exposure to viral antigens. However, the immune correlates of different clinical stages of cHBV and their relation with different levels of HBsAg have not been investigated. The aim of the present study was to evaluate the relationship between HBV-specific T cells response and the degree of in vivo HBV control and HBsAg serum levels in HBeAg-HBeAb+ cHBV. METHODS: Peripheral blood mononuclear cells from 42 patients with different clinical profiles (treatment-suppressed, inactive carriers and active hepatitis) of cHBV, 6 patients with resolved HBV infection and 10 HBV-uninfected individuals were tested with overlapping peptides spanning the entire HBV proteome. The frequency and magnitude of HBV-specific T cell responses was assessed by IFNγ ELISPOT assay. Serum HBsAg was quantified with a chemiluminescent immunoassay. RESULTS: The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups. However, inactive carriers targeted preferentially the core region. In untreated patients, the breadth of the anti-core specific T cell response was inversely correlated with serum HBsAg concentrations as well as HBV-DNA and ALT levels and was significantly different in patients with HBsAg levels either above or below 1000 IU/mL. The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients. CONCLUSIONS: Different clinical outcomes of cHBV infection are associated with the magnitude, breadth and specificity of the HBV-specific T cell response. Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.