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Abstract Background Immunotargets including checkpoint inhibitors and toll-like receptor 8 agonists have recently gained attention for the recovery of hepatitis B virus (HBV)-specific T cell exhaustion in chronic hepatitis B(CHB). Chemokine receptors have a similar significant role during viral infections; however, their role in CHB remains poorly understood. Therefore, in this study we evaluated the role of chemokine receptor 4 (CCR4) in deriving immunosuppression during CHB. Methods We characterized CCR4+CD8+ T cells in CHB and identified their involvement in immunosuppression. Further, we examined if CCR4 blockade with mogamulizumab antibody can recover the functional exhaustion in HBsAg-specific T cells. Results CHB patients exhibit higher frequency of CCR4+CD8+ T cells that increase with higher HBsAg levels and fibrosis scores. In vitro, HBs antigen triggers CCR4 expression. These cells express multiple inhibitory receptors and exhibit immunosuppressive functions by producing excessive immunoregulatory cytokines IL-4, IL-5, IL-10 and TGF-β1. CCR4 Blockade significantly boosted HBsAg-specific antiviral-cytokine production(IFN-γ, TNF-α and IL-21) in T cells through enhancing their proliferation capacity and polarizing these cells towards T helper 1(Th1) and T follicular helper cells(TFH) in case of CD4 cells, and cytotoxic T cell 1(TC1) and cytotoxic T follicular(TCF) cells in case of CD8. Cytotoxic potential was improved, while no induction of immunosuppressive-cytokines was seen after anti-CCR4 treatment thereby eliminating the risk of treatment-induced immunosuppression. CCR4 blockade inhibited the development and effector function of Tregs by controlling their expansion and TGF-β1 production preventing Tregs-induced immunotolearance. Conclusions CCR4 blockade reconstitutes antiviral immune response in T cells and limits the immunosuppressive functions of Tregs, representing them as a promising immunotherapeutic target for functional cure of CHB.

Abstract Objectives Primary Objective: To evaluate the efficacy and safety of oral administration of imatinib combined with the Best Conventional Care (BCC) versus placebo plus BCC in hospitalized patients with COVID-19. Hypothesis: Addition of imatinib to the BCC will provide a superior clinical outcome for patients with COVID-19 compared with BCC plus placebo. This hypothesis is on the basis of 1) intralysosomal entrapment of imatinib will increase endosomal pH and effectively decrease SARS-CoV-2/cell fusion, 2) kinase inhibitory activity of imatinib will interfere with budding/release or replication of SARS-CoV-2, and 3) because of the critical role of mechanical ventilation in the care of patients with ARDS, imatinib will have a significant clinical impact for patients with critical COVID-19 infection in Intensive Care Unit (ICU). Trial design This is an individual patient-level randomized, double-blind, placebo-controlled, two-parallel arm phase 3 study to evaluate the safety and efficacy of imatinib for the treatment of hospitalized adults with COVID-19. Participants will be followed for up to 60 days from the start of study drug administration. This trial will be conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. Participants Inclusion Criteria: Patients may be included in the study only if they meet all of the following criteria: 1) Ability to understand and willingness to sign a written informed consent document. Informed consent must be obtained prior to participation in the study. For patients who are too unwell to provide consent such as patients on invasive ventilator or extracorporeal membrane oxygenation (ECMO), their Legally Authorized Representative (LAR) can sign the informed consent, 2) Hospitalized patients ≥18 years of age, 3) Positive reverse transcriptase-polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 in the respiratory tract sample (oropharyngeal, nasopharyngeal or bronchoalveolar lavage (BAL)) by Center for Disease Control or local laboratory within 7 days of randomization, 4) Women of childbearing potential must agree to use at least one primary form of contraception for the duration of the study. Exclusion Criteria: Patients meeting any of the following criteria are not eligible for the study: 1) Patients receiving any other investigational agents in a clinical trial. Off-label use of agents such as hydroxychloroquine is not an exclusion criterion, 2) Pregnant or breastfeeding women, 3) Patients with significant liver or renal dysfunction at the time of screening as defined as: 3.1) Direct bilirubin >2.5 mg/dL, 3.2) AST, ALT, or alkaline phosphatase >5x upper limit of normal, 3.3) eGFR ≤30 mL/min or requiring renal replacement therapy, 4) Patients with significant hematologic disorder at screen as defined as: 4.1) Absolute neutrophil count (ANC)