Immunomodulation Induced During Interferon-α Therapy Impairs the Anti-HBV Immune Response Through CD24+CD38hi B Cells

Fu, Binqing; Wang, Dongyao; Shen, Xiaokun; Guo, Chuang; Liu, Yanyan; Ye, Ying; Sun, Rui; Li, Jiabin; Tian, Zhigang; Wei, Haiming

doi:10.3389/fimmu.2020.591269

Cited by 13 publications

(21 citation statements)

References 47 publications

(58 reference statements)

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“…PBMC of these patients were stimulated with HBsAg. 14,48 We found that the proportions of IFN-γ + CD8 + T cells and CD107a + CD8 + T cells were significantly increased at the +24 w timepoint, following IL-2 therapy initiation (Fig. 5b-d).…”

Section: Il-2 Therapy Increases the Expansion And Responses Of Hbvspecific Cd8 + T Cells In Nr (α-2b) Patients In Vivomentioning

confidence: 84%

“…13 What's more, we determined that IFN-α therapy for persistent HBV infection in humans may induce an immunomodulatory effect in chronic HBV patients by significantly upregulating levels of CD24 + CD38 hi B cells, which could drive an immunosuppressive program and reduce antiviral effects. 14 Suppressive mechanisms, such as the activity of regulatory T cells (Tregs) and programmed cell death protein 1 (PD-1) expression, have been demonstrated to occur during HBV infection. [15][16][17][18] However, the modulation of these inhibitory pathways in vitro has led to effective functional recovery in only a minority of patients with chronic hepatitis B (CHB).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Shen

et al. 2021

Sig Transduct Target Ther

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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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Section: Il-2 Therapy Increases the Expansion And Responses Of Hbvspecific Cd8 + T Cells In Nr (α-2b) Patients In Vivomentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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

Wang

Shen

et al. 2021

Sig Transduct Target Ther

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“…IFN-I suppresses HBV replication when viral load is high and enhances HBV replication when viral load is low via transcriptional and post-transcriptional regulations ( Tian et al, 2011 ). However, some patients suffer from IFN-α treatment resistance by inducing CD24 + CD38 hi B cell and IFN-α/γ-STAT1-PD-L1 axis-mediated downregulating functions of T cells and NK cells ( Fu et al, 2020 ; Liu et al, 2020 ) as well as producing anti-IFN-α Abs ( Porres et al, 1989 ).…”

Section: Cytokines In Hepatitis B Virus Infectionmentioning

confidence: 99%

Cytokines and Chemokines in HBV Infection

Zhong

Zhang

Tang

et al. 2021

Front. Mol. Biosci.

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Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatic inflammation and damage. The pathogenesis of chronic hepatitis B (CHB) infection is predominantly mediated by persistent intrahepatic immunopathology. With the characterization of unique anatomical and immunological structure, the liver is also deemed an immunological organ, which gives rise to massive cytokines and chemokines under pathogenesis conditions, having significant implications for the progression of HBV infection. The intrahepatic innate immune system is responsible for the formidable source of cytokines and chemokines, with the latter also derived from hepatic parenchymal cells. In addition, systemic cytokines and chemokines are disturbed along with the disease course. Since HBV is a stealth virus, persistent exposure to HBV-related antigens confers to immune exhaustion, whereby regulatory cells are recruited by intrahepatic chemokines and cytokines, including interleukin-10 and transforming growth factor β, are involved in such series of causal events. Although the considerable value of two types of available approved treatment, interferons and nucleos(t)ide analogues, effectively suppress HBV replication, neither of them is sufficient for optimal restoration of the immunological attrition state to win the battle of the functional or virological cure of CHB infection. Notably, cytokines and chemokines play a crucial role in regulating the immune response. They exert effects by directly acting on HBV or indirectly manipulating target immune cells. As such, specific cytokines and chemokines, with a potential possibility to serve as novel immunological interventions, combined with those that target the virus itself, seem to be promising prospects in curative CHB infection. Here, we systematically review the recent literature that elucidates cytokine and chemokine-mediated pathogenesis and immune exhaustion of HBV infection and their dynamics triggered by current mainstream anti-HBV therapy. The predictive value of disease progression or control and the immunotherapies target of specific major cytokines and chemokines in CHB infection will also be delineated.

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“…Pegylated interferon α‐2b initiates an immunosuppressive response centered on CD24 + CD38 hi B cells, including the downregulation of both T‐ and NK‐cell functions. Patients with low levels of CD24 + CD38 hi B cells were associated with improved therapeutic outcomes (Fu et al, 2020). In particular, the use of anti‐CD24 antibodies to deplete CD24 + CD38 hi B cells without compromising other B‐cell subsets suggests a promising strategy for improving therapeutic efficacy.…”

Section: Targeted Cd38 For B‐cell Diseasesmentioning

confidence: 99%

“…Pegylated interferon α-2b initiates an immunosuppressive response centered on CD24 + CD38 hi B cells, including the downregulation of both T-and NK-cell functions. Patients with low levels of CD24 + CD38 hi B cells were associated with improved therapeutic outcomes (Fu et al, 2020). In particular, the use of anti-CD24…”

Section: Disease Name Cd38 Expression Diagnosis and Prognosis Referencesmentioning

confidence: 99%

Effect of CD38 on B‐cell function and its role in the diagnosis and treatment of B‐cell‐related diseases

Zeng

Zhang

Jin

et al. 2022

Journal Cellular Physiology

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CD38 is a multifunctional receptor and enzyme present on the surface of B lymphocytes, which can induce B lymphocytes proliferation and apoptosis by crosslinking related cytokines to affect the function of B cells, thus affecting immune regulation in humans and promoting tumorigenesis. The level of CD38 expression in B cells has become an important factor in the clinical diagnosis, treatment, and prognosis of malignant tumors and other related diseases. Therefore, studying the relationship between CD38 expression on the surface of B cells and the occurrence of the disease is of great significance for elucidating its association with disease pathogenesis and the clinical targeted therapy. In this paper, we review the effects of CD38 on B‐cell activation, proliferation, and differentiation, and elaborate the functional role and mechanism of CD38 expression on B cells. We also summarize the relationship between the level of CD38 expression on the surface of B cells and the diagnosis, treatment, and prognosis of various diseases, as well as the potential use of targeted CD38 treatment for related diseases. This will provide an important theoretical basis for the scientific research and clinical diagnosis and treatment of B‐cell‐related diseases.

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Immunomodulation Induced During Interferon-α Therapy Impairs the Anti-HBV Immune Response Through CD24+CD38hi B Cells

Cited by 13 publications

References 47 publications

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

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

Cytokines and Chemokines in HBV Infection

Effect of CD38 on B‐cell function and its role in the diagnosis and treatment of B‐cell‐related diseases

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