The recent progress in T-cell-based therapies for tumor treatment is encouraging and provides therapeutic guidance for major chronic viral infections with HIV and HBV

The recent progress in T-cell-based therapies for tumor treatment is encouraging and provides therapeutic guidance for major chronic viral infections with HIV and HBV. such as arginase (33) and IDO (34) are released by damaged hepatocytes Rabbit Polyclonal to E-cadherin and cause depletion of amino acids, which are important in maintaining T cell functions (35). Arginine depletion prospects to reduction of CD3 levels in T cells, subsequently causing TCR-pathway dysfunction (36). Intrahepatic inflammation recruits regulatory T cells (37C41), B cells, and myeloid-derived suppressor cells (42C44), and activate stellate cells, leading to IL-10 and TGF- production (25). The suppressive events in the liver are vital for protection from severe damage primed by inflammation, while further impairing the functionality of HBV-specific T cells. In general, high HBV DNA, HBsAg, and HBeAg levels contribute to maintain HBV-specific immune tolerance in chronically HBV-infected individuals. Reduction of both circulating and intrahepatic HBV virions and proteins is usually a prerequisite for (re-)establishing efficient HBV-specific T-cell responses (45C48). The first evidence that HBV clearance can be achieved by adoptive transfer of bone marrow from anti-HBs-positive donors (49) provides a certain way to remedy HBV contamination through immune modulation. Liver transplantation may also transfer immune cells from vaccinated donors to recipients, and partially control reinfection of the liver (50). An increasing number of studies have been carried out to explore therapeutic strategies including those including small molecules to boost HBV immunity in patients, aiming to a functional remedy for HBV contamination SIRT-IN-1 (51C53). Therapeutic Strategies for CHB Based on the knowledge about the immune pathogenesis of chronic HBV infection, a number of innovative strategies may be applied to enhance HBV-specific immune SIRT-IN-1 responses in patients (Physique 1). On one hand, oral, intranasal, or subcutaneous application of agonists of pathogen acknowledgement receptors (PRRs), including TLRs, retinoic acid-inducible gene 1 (RIG-I), and stimulator of interferon genes (STING), activates host immune cells and hepatocytes/non-parenchymal liver cells, leading to the production of IFN/expression of interferon-stimulated genes (ISGs) and proinflammatory cytokines, which jointly mount an antiviral state (Physique 2). On the other hand, HBV-specific CTLs can be induced by therapeutic vaccines, boosted through checkpoint blockade, or renewed by adoptive transfer of activated T/NKT cells or genetically edited HBV-specific T cells such as chimeric antigen receptor T (CAR-T) or T cell SIRT-IN-1 receptor (TCR)-T cells (Physique 3). These strategies have been explored in the past years. Though their potential usefulness is usually partly confirmed, many hurdles hindering the clinical use of these methods are still to be overcome in the future. Open in a separate window Physique 1 Methods for the treatment of chronic HBV contamination. Available knowledge about HBV immune control and immunopathogenesis; a number of immunomodulatory strategies have been tested to enhance innate and adaptive immunity in preclinical models and clinical trials. TLR, toll-like receptor; RIG-I, retinoic acid-inducible gene 1; STING, stimulator of interferon genes; APOBEC, apolipoprotein B mRNA-editing enzyme catalytic subunit; PBMC, peripheral blood mononuclear cell; DC, dendritic cell; CIK, cytokine-induced killer; CAR-T, chimeric antigen receptor T-cell; TCR, T cell receptor. Dots in various colors show different cytokines. Open in a separate window Physique 2 Options for enhancing innate immunity and establish an antiviral state. Oral, intranasal, or subcutaneous application of agonists of PARs, including TLRs, RIG-I, and STING, activates host immune cells and hepatic parenchymal and non-parenchymal cells, leading to the production of IFN and proinflammatory cytokines as SIRT-IN-1 well as ISG expression. TLR, toll-like receptor; RIG-I, retinoic acid-inducible gene 1; STING, stimulator of interferon genes; NF-B, nuclear factor kappa-B; ISG, interferon-stimulated gene; cGAS, cyclic GMP-AMP synthetase. Dots in various colors show different cytokines. STING expression in hepatocytes remains controversial. Open in a separate window Physique 3.

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