HBV免疫随年龄相关原因 IL21和OX40

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小孩免疫耐受，成人急性感染被清除的很大原因，和OX40及IL21有关系

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【标题】：OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection
【作者】：Jacobi, F. J.; Wild, K.; Smits, M. (...)
【来源】：Journal of Hepatology, 2019, 70(6), 1103-1113
【摘要】：BACKGROUND & AIMS: Current antiviral therapies lack the potential to eliminate persistent HBV infection. HBV-specific T cells are crucial for HBV control and have recently been shown to be protective in patients following discontinuation of antiviral therapy. Thus, T cell-based approaches may greatly improve the therapeutic landscape of HBV-infection. We aimed to augment HBV-specific CD4 T cells from chronically infected patients by targeting different immunological pathways. METHODS: Expression of various co-stimulatory and inhibitory receptors  on HBV- and Influenza-specific CD4 T cells was analyzed directly ex vivo by MHC class II-tetramers. HBV-genotype D infected patients were screened for CD4 T cell responses by IFN-gamma ELISpot and intracellular cytokine staining following stimulation with overlapping peptides (OLPs) spanning the HBV-polyprotein. Stimulation with recombinant IL-7, an agonistic OX40-antibody or blockade of PD-L1 was performed in antigen-specific in vitro cultures. Cytokine secretion and expression of transcription factors were analyzed by flow cytometry. Responses targeting Influenza, Epstein-Barr virus and tetanus toxoid served as controls. RESULTS: Tetramer-staining revealed that the IL-7 receptor-alpha (CD127), OX40 and PD-1 constitute possible therapeutic targets as they were all strongly expressed on HBV-specific CD4 T cells ex vivo. The HBV-specific CD4 T cell responses identified by OLP-screening targeted predominantly the HBV-polymerase and core proteins. Combined OX40 stimulation and PD-L1 blockade significantly augmented IFN-gamma and IL-21 producing HBV-specific CD4 T cells in vitro, suggesting active Th1 and follicular T helper cell programs. Indeed, transcription factors T-bet and Bcl6 were strongly expressed in cytokine producing cells. CONCLUSIONS: Combined OX40 stimulation and PD-L1 blockade augmented secretion of the helper T cell signature cytokines IFN-gamma and IL-21, suggesting that immunotherapeutic approaches can improve HBV-specific CD4 T cells. LAY SUMMARY: CD4 T cells are important in controlling viral infections, but are impaired in the context of chronic HBV-infection. Therapeutic approaches  to cure chronic HBV-infection are highly likely to require an immune-stimulatory  component. This study demonstrates that HBV-specific CD4 T cells can be functionally augmented by combined stimulation of the costimulatory molecule OX40 and blockade of the inhibitory PD-1 pathway.

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【标题】：An OX40/OX40L interaction directs successful immunity to hepatitis B virus
【作者】：Publicover, J.; Gaggar, A.; Jespersen, J. M. (...)
【来源】：Sci Transl Med, 2018, 10(433),
【摘要】：Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator. Using an age-dependent mouse model of HBV clearance and persistence in conjunction with human blood and liver tissue, we studied mechanisms of viral clearance to identify new therapeutic targets. We demonstrate that age-dependent  expression of the costimulatory molecule OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to improved HBV antigen clearance in young mice, as well as increased strength of T cell responses in young mice and adult mice that were exposed to HBV when they were young and developed a CHB serological profile. Similarly, in humans, we show that hepatic OX40L transcript expression is age-dependent and that increased OX40 expression on peripheral CD4(+) T cells in  adults is associated with HBV clearance. These findings provide new mechanistic understanding of the immune pathways and cells necessary for HBV immunity and identify potential therapeutic targets for resolving CHB.

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【标题】：IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B
【作者】：Publicover, J.; Goodsell, A.; Nishimura, S. (...)
【来源】：J Clin Invest, 2011, 121(3), 1154-1162
【摘要】：HBV is a noncytopathic hepadnavirus and major human pathogen that causes immune-mediated acute and chronic hepatitis. The immune response to HBV antigens  is age dependent: viral clearance occurs in most adults, while neonates and children usually develop chronic infection and liver disease. Here, we characterize an animal model for HBV infection that recapitulates the key differences in viral clearance between early life and adulthood and find that IL-21 may be part of an effective primary hepatic immune response to HBV. In our  model, adult mice showed higher HBV-dependent IL-21 production in liver, compared with that of young mice. Conversely, absence of the IL-21 receptor in adult mice  resulted in antigen persistence akin to that of young mice. In humans, levels of  IL-21 transcripts were greatly increased in blood samples from acutely infected adults who clear the virus. These observations suggest a different model for the  dichotomous, age dependent outcome of HBV infection in humans, in which decreased IL-21 production in younger patients may hinder generation of crucial CD8+ T and  B cell responses. These findings carry implications for therapeutic augmentation  of immune responses to HBV and potentially other persistent liver viruses.