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

Abstract

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-naïve; 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.

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Cytomegalovirus-specific neutralizing antibodies effectively prevent uncontrolled infection after allogeneic hematopoietic stem cell transplantation

“…Freshly isolated PBMCs were resuspended and seeded in 24 well plates in RPMI 1640 medium (Gibco) supplemented with 10% fetal bovine serum (FBS, Gibco) and penicillin (100 U/mL)/streptomycin (100 μg/mL). Cells were stimulated with ionomycin (1μg/mL, Calbiochem) and phorbol 12-myristate 13-acetate (PMA) (50ng/mL, Sigma) or HLA-restricted CMV pp65 peptides ( key resources table ) in the presence of monensin (10μg/mL, Sigma) for 4hat 37°C and 5% CO 2 , as previously described ( Wang et al., 2021 ). Stimulated cells were collected and stained with monoclonal antibodies (mAbs, key resources table ) against CD45, CD3, CD56, and CD8, followed by permeabilization (eBioscience) for 20 min at 20°C, and then stained with mAbs ( key resources table ) against interferon-γ (IFN-γ) and tumor necrosis factor alpha (TNF-α) ( Wang et al., 2019 ).…”