Chronic hepatitis B virus (HBV) infection is endemic in the Asian-Pacific region, and reactivation of HBV post-cancer chemotherapy has become an emerging clinical challenge. Patients with detectable serum HBV DNA before chemotherapy and those receiving intensive chemotherapy are particularly at a risk of HBV reactivation. Most patients with HBV reactivation are positive for hepatitis B surface antigen (HBsAg) and are, therefore, easily identified by recommended serological screening before chemotherapy. However, a small, but significant proportion of subjects who have apparently recovered from HBV infection as reflected by HBsAg negativity and hepatitis B core antibody positivity in HBV endemic areas may also experience reactivation when host immunity is severely compromised by cancer chemotherapy. Serum alanine aminotransferase, HBsAg, and/or HBV DNA should be monitored closely in these subjects and antiviral therapy should be administered immediately when any evidence of HBV reactivation is detected during chemotherapy. The prophylactic use of nucleos(t)ide analogs before chemotherapy and its continuation until reconstitution of host immunity remain the mainstay of effective prevention of hepatitis B reactivation in this special clinical entity.

Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.21442

Ethanol-induced oxidative stress suppresses generation of peptides for antigen presentation by hepatoma cells.

Autoreactivity may play a critical role in the chronification of atopic dermatitis (AD). Several studies showed that AD patients produce IgE Abs specific for autoantigens, and we described Th as well as CD8(+) T cells specific for the autoallergen Hom s 2, the α-chain of the nascent polypeptide-associated complex (α-NAC). This study aimed to investigate the frequency and inflammatory phenotype of autoallergen-specific CD8(+) T cells. CD8(+) T cell immunodominant epitopes of α-NAC were mapped by applying prediction softwares, and binding affinity was confirmed by stabilization of empty MHC complexes. MHC class I tetramers were assembled and binding cells were analyzed directly ex vivo by flow cytometry and in terms of single-cell assessment by ChipCytometry. We report significantly elevated numbers of α-NAC-specific peripheral T cells in sensitized patients compared with nonatopic controls. These cells secrete IL-4 and IFN-γ, and surface markers revealed significantly elevated frequencies of circulating terminally differentiated α-NAC-specific CD8(+) T cells in patients with AD compared with nonatopic donors. The observed phenotype of α-NAC-specific CD8(+) T cells indicates a role in the pathogenesis of AD.

α-NAC–Specific Autoreactive CD8+ T Cells in Atopic Dermatitis Are of an Effector Memory Type and Secrete IL-4 and IFN-γ

Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naive; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.

Restoration of HBV-specific CD8+ T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy.

Background and Aims

Acute exacerbation (AE) of chronic hepatitis B virus (HBV) infection is common and negatively impacts the clinical outcome. Although upsurge of viral load always precedes or coincides with AE, the underlying immunological mechanisms remain unclear and were investigated.



Methods

We prospectively followed the serum cytokine/chemokine profiles, viral load, and alanine aminotransferase (ALT) levels in 250 patients and identified 44 consecutive patients (male: 72.7%; age: 40.4 ± 9.7 years; hepatitis B e antigen [HBeAg] positivity: 63.6%; genotype B/C: 75%/25%) who developed AE during the follow-up in a medical center. The impact of clinical characteristics (age, gender, HBeAg, ALT, HBV genotype), cytokines (tumor necrosis factor-alpha, interferon gamma, interleukin [IL]-2, IL-4, IL-6, and IL-10), and chemokines (CXCL10/interferon gamma-induced protein [IP]-10, CCL2/MCP-1, CXCL9/MIG, CCL5/RANTES, and CXCL8/IL-8) on the serum HBV DNA dynamics at different time points (baseline, peak of serum HBV DNA level, peak of serum ALT level, and after AE) were analyzed.



Results

Of 44 patients, serum HBV DNA level surged before the peak of serum ALT level in 23 (52.3%), and coincided with the peak of ALT in 21 (47.7%). The upsurge of serum viral load significantly correlated with the increase of IL-10 (P = 0.0037) and CXCL10/IP-10 (P = 0.0044). Upsurge of serum viral load was preceded by an increase in serum IL-4 (P < 0.05), IL-6 (P < 0.05), and IL-10 (P < 0.05). Combination of HBV genotype, IL-6 level at baseline, and ALT level at the peak of serum HBV DNA reliably predicted subsequent AE pattern (P = 0.0116).



Conclusions

Enhanced Th2 activity is likely involved in the surge of HBV DNA level before hepatitis exacerbation.

Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: Clinical and mechanistic implications

Frequencies of epitope-specific cytotoxic T lymphocytes in active chronic viral hepatitis B infection by using MHC class I peptide tetramers

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Frequencies of epitope-specific cytotoxic T lymphocytes in active chronic viral hepatitis B infection by using MHC class I peptide tetramers