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    Home > Active Ingredient News > Immunology News > Gut(IF=32) Peng Hua/Tsinghua University of Chinese Academy of Sciences Fu Yangxin discovered a potential new method to disrupt HBV immune tolerance

    Gut(IF=32) Peng Hua/Tsinghua University of Chinese Academy of Sciences Fu Yangxin discovered a potential new method to disrupt HBV immune tolerance

    • Last Update: 2022-11-04
    • Source: Internet
    • Author: User
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    iNature

    High hepatitis B virus (HBV) antigen load and high levels of programmed death ligand 1 (PDL1) in the liver lead to immune tolerance
    to HBV.
    Type I interferon (IFN) is the most potent antiviral cytokine and greatly enhances cross-presentation and T cell activation in dendritic cells (DCs
    ).
    However, frequent repeated administration of IFN can cause systemic toxicity, induce PDL1 expression, and inhibit T cell responses
    .
    In the absence of the protective immunity needed to eradicate HBV, it is common
    for chronic hepatitis B (CHB) to recur after completing antiviral therapy.

    On October 31, 2022, Peng Hua, a biophysics researcher of the Chinese Academy of Sciences, and Fu Yangxin of Tsinghua University, jointly published a joint communication entitled "Engineered anti- PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV" online in Gut (IF=32).
    immune tolerance", which developed an anti-PDL1-based interferon (IFN) fusion protein to overcome chronic hepatitis B virus (HBV)-induced immune tolerance and combined this immunotherapy with HBV vaccine to achieve a functional cure
    for chronic hepatitis B (CHB) infection.

    The results showed that anti-PDL1-IFNα heterodimers preferentially targeted the liver, resulting in viral suppression, PD1/PDL1 immune checkpoint blockade, and dendritic cell activation/antigen presentation activation of HBsAg-specific T cells, thereby breaking the immune tolerance
    of chronic HBV carrier mice 。 When the HBsAg vaccine was administered shortly after anti-PDL1-IFNα heterodimer therapy, the authors observed that anti-HBsAg antibodies and HBsAg-specific T cell responses that effectively cleared HBsAg were effectively cleared in chronic HBV-carrying mice receiving combination therapy, but not
    in chronic HBV-carrying mice receiving monotherapy.
    Anti-PDL1-IFNα heterodimers targeting the liver can disrupt HBV-induced immune tolerance to HBsAg vaccines, providing a promising translational therapeutic strategy
    for the functional cure of CHB.

    Although effective vaccines against hepatitis B virus (HBV) have been available since the 90s of the 20th century, an estimated 257 million people worldwide have chronic HBV infection, which poses a high risk of
    developing fibrosis, cirrhosis and hepatocellular carcinoma (HCC).
    Chronic hepatitis B (CHB), characterized by the loss of hepatitis B surface antigen (HBsAg) and HBV-DNA in serum and its conversion to anti-HBsAg, is a challenging endpoint
    of current CHB treatment.
    HBsAg serum clearance after anti-HBV therapy is associated
    with a significant reduction in HCC morbidity and mortality.
    Type I interferons (IFNs) are approved drugs that are not effective in reducing viral antigen load, and it is difficult to maintain sustained viral control
    after discontinuation.
    However, long-term repeated high-dose interferon therapy can cause systemic toxicity
    .
    In addition, IFNs can upregulate the expression of immunosuppressive molecular programmed death ligand 1 (PDL1), thereby inhibiting the antiviral immune response and gradually reducing the therapeutic effect
    .
    How to overcome systemic toxicity caused by IFNs and subsequent immunosuppression remains to be solved
    .
    The liver is an immune tolerant organ, especially in patients with
    chronic hepatitis B.
    PDL1 in the liver of CHB patients is significantly upregulated, biasing the immune response towards inducing tolerance of circulating naïve T cells and attenuating the effector function
    of hepatic infiltrating cytotoxic T lymphocytes (CTLs).
    Conditionally knocking out PDL1 in dendritic cells (DCs) can release these inhibitions, leading to better T cell activation
    .
    To date, programmed death1 (PD1)/PDL1 blockade therapy has been shown to induce an anti-tumor response
    in a small percentage of cancer patients.
    In addition, several studies have reported that PD1/PDL1 blockade can partially restore HBV-specific T or B cell function
    in vitro.
    However, the functional cure rate for CHB patients treated with PD1 inhibitors (nivolumab) is quite low
    .
    PD1/PDL1 inhibitors enhance the ability of CTLs to kill infected hepatocytes and release a variety of viruses to infect healthy hepatocytes
    .
    Killing infected cells while stopping viral reinfection is a challenge
    .
    High concentrations of viral antigens circulating in the blood impair the function of DC and natural killers as well as HBV-specific T and B cells, thereby radically eliminating the host immunity
    required for HBV.
    T cells encounter poor HBV antigen from DCs in the liver, which may lead to immune tolerance rather than functional activation
    .
    The authors propose that
    simultaneous suppression of viral load and enhancement of antigen presentation may require breaking tolerance to induce anti-HBV immunity
    .
    Anti-PDL1-IFNα heterodimer combined with hepatitis B surface antigen inoculation produces functional cure in HBV-carrying mice (Figure from Gut) The authors took advantage of the high expression of PDL1 in the liver of CHB patients and chronic HBV-carrying mice to target IFNα with anti-PDL1-IFNα and PDL1 and type I IFN receptors (IFNAR) in the liver, Thus overcoming PDL1-mediated local resistance and virus production
    .
    Importantly
    , the anti-PDL1-IFNα multifunctional fusion protein can overcome the resistance of chronic HBV carrier mice to HBsAg vaccine, generate strong anti-HBsAg neutralizing antibody (NAb) and HBsAg-specific T cell response, and achieve functional cure
    of mouse CHB.
    Original link: https://gut.
    bmj.
    com/content/early/2022/10/31/gutjnl-2022-327059?rss=1

    END

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