AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral ...AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25+CD4+ regulatory T (Treg) cells might be involved in a inhibition of CD8+T cell priming or in the modulation of the magnitude of the 'peak' antiviral CD8+ T cell response primed by DNA immunization. METHODS: B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 μg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25+ cells. Induction of HBV-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-γ staining. RESULTS: DNA immunization induced HBV-specific CD8+ T cells. At the peak T cell response (d 10), 7.1±2.0% of CD8+ T cells were HBV-specific after DNA immunization, whereas 12.7±3.2% of CD8+ T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8+ T cells in the absence of CD25+ Treg cells (n = 6, P<0.05). Similarly, fewer HBV specific memory T cells were detected in the presence of these cells (1.3±0.4%) in comparison to Treg-depleted mice (2.6±0.9%) on d 30 after DNA immunization (n - 6, P<0.01). Both IFN-γ production and the avidity of the HBV-specific CD8+ T cell response to antigen were higher in HBV-specific CD8+ T cells induced in the absence of Treg cells. CONCLUSION: CD25+ Treg cells suppress priming and/or expansion of antigen-specific CD8+ T cells during DNA immunization and the peak CD8+ T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8+ T cell response and may affect the quality of memory T cell pools. The elimination of Treg cells or their inhibition may be important in immunotherapeutic strategies to control HBV infection by inducing virus-specific cytotoxic T lymphocyte responses in chronically infected subjects.展开更多
The functional roles of memory B and T lymphocytes underlie the phenomenal success of prophylactic vaccinations, which have decreased morbidities and mortalities from infectious diseases globally over the last 50 year...The functional roles of memory B and T lymphocytes underlie the phenomenal success of prophylactic vaccinations, which have decreased morbidities and mortalities from infectious diseases globally over the last 50 years. However, it is becoming increasingly appreciated that memory cells are also capable of mediating the pathology associated with autoimmune disorders and transplant rejection, and may pose a significant barrier to future clinical advancement in immunoregulation. Therefore, understanding the unique properties of memory lymphocytes （as compared to their naive precursors） is a major area of investigation. Here, we focus on one of those singular properties of memory T cells （TM）-rapid recall. As will be discussed in more detail, rapid recall refers to the ability of quiescent TM cells to efficiently and robustly express‘effector functions＇ following stimulation. Studies that have advanced our understanding of TM cells＇ rapid recall using CD4^＋ T cells have been expertly reviewed elsewhere, so we will focus primarily on studies of CD8^＋ T cells. We will first review the different ways that CD8^＋ TM cells can be generated, followed by discussing how this influences their functional properties in the settings of immune protection and pathology. Then, rapid recall ability will be discussed, with emphasis placed on what is currently known about the mechanisms that underlie this unique property of TM cells.展开更多
Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epit...Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.展开更多
ABM: This study aims at exploring the distribution of TCM syndromes in CHB patients with HBV pre-core mutation (1896) and the relationship between pre-core mutation and T lymphocytes subgroup, through which to provide...ABM: This study aims at exploring the distribution of TCM syndromes in CHB patients with HBV pre-core mutation (1896) and the relationship between pre-core mutation and T lymphocytes subgroup, through which to provide objective data on clinical syndrome differentiation of TCM, and further to suggest the therapeutic principle and guide clinical treatment. METHODS: One hundred and forty CHB patients were evenly divided into two study groups, HBV pre-core mutant group and HBV pre-core wild-type group. Besides, 30 healthy blood donors were selected as a healthy control group. HBV-labeled compound, T lymphocytes subgroup, and HBV-DNA pre-core mutant were tested in the study groups. T lymphocytes subgroup were also tested in the control group. All the patients were both diagnosed by syndrome differentiation of TCM and western medicine. RESULTS: The most common syndrome in mutant group was damp-heat combined with blood stasis, and the most common syndrome in the wild-type group was damp-heat stasis in the middle-jiao. There were more cases of medium and severe hepatitis in mutant group than that in wild-type group. The content of CD4+ lymphocytes and CD4+/CD8+ ratio were decreased gradually (healthy control group>wild-type group>mutant group). In the wild-type group, severe and medium CHB patients had considerably lower level of them than mild CHB patients. However, in the mutant group, the opposite result appeared. Meanwhile, the content of HBV-DNA in mutant group was higher than that in wild-type group. CONCLUSION: Damp, heat, toxin and blood stasis were the basic pathogens of CHB, whether pre-core mutant or not. CHB with precore mutant may lead to more severe hepatitis. The decreased content of CD4+ lymphocytes and ratio of CD4+/CD8+ may be taken as one of the indices in confirming the deficiency syndrome of CHB patients with pre-core mutation.展开更多
OBJECTIVE: To evaluate the effect of Fuzhengpaidu granule (FZPDG) on immune activation molecules CD38 and human leukocyte antigen-D related (HLA-DR) on CD4+ and CD8+ cells in HIV/AIDS patients, and to explore the unde...OBJECTIVE: To evaluate the effect of Fuzhengpaidu granule (FZPDG) on immune activation molecules CD38 and human leukocyte antigen-D related (HLA-DR) on CD4+ and CD8+ cells in HIV/AIDS patients, and to explore the underlying mechanism of this therapy. METHODS: Plasma changes in CD3+, CD4+, CD8+, CD3+CD4+CD38+, CD3+CD4+HLA-DR+, CD3+ CD8+CD38+, and CD3+CD8+HLA-DR+levels in HIV/ AIDS patients treated with FZPDG for six months were examined by flow cytometry and compared with levels in healthy controls. RESULTS: The clinical trial included 34 outpatients with HIV/AIDS. Before treatment, plasma levels of CD38+ and HLA-DR+ on CD4/CD8 cells were higherthan those in 28 health controls (P<0.05). There were no significant changes in serum levels of CD3+, CD4+, and CD8+ T cells between pretreatment baseline versus after treatment, which were 82.85% ± 5.41% , 14.57% ± 10.31% and 54.55% ± 11.43% before treatment and 79.15% ± 8.21% , 19.96% ± 9.58% and 56.36% ± 11.67% after treatment, respectively (P>0.05). Plasma levels of CD3+ CD4+CD38+and CD3+CD4+HLA-DR+were 2.3%± 2.2% and 7.8%±5.5% before treatment and 1.2%± 0.8% and 2.6%±1.0% after treatment, respectively. Plasma levels of CD3+CD8+CD38+ and CD3+CD8+ HLA-DR+ were 41.4%±13.4% and 17.8%±11.3% beforetreatment,whichchangedto27.1%±10.2%and 3.8%±2.4%aftertreatment,respectively(P<0.05). CONCLUSION: HIV/AIDS patients exhibited an immune activation profile following FZPDG treatment. A potential mechanism of action for FZPDG appears to lie in its ability to up-regulate CD38 and HLA-DR levels on CD4+ T cells, and down-regulate them on CD8+ cells, thereby modulating immune activation of CD4+and CD8+T cells.展开更多
基金Supported by in part Grant-in-Aid for Scientific Research (C) (toK.K)
文摘AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25+CD4+ regulatory T (Treg) cells might be involved in a inhibition of CD8+T cell priming or in the modulation of the magnitude of the 'peak' antiviral CD8+ T cell response primed by DNA immunization. METHODS: B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 μg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25+ cells. Induction of HBV-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-γ staining. RESULTS: DNA immunization induced HBV-specific CD8+ T cells. At the peak T cell response (d 10), 7.1±2.0% of CD8+ T cells were HBV-specific after DNA immunization, whereas 12.7±3.2% of CD8+ T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8+ T cells in the absence of CD25+ Treg cells (n = 6, P<0.05). Similarly, fewer HBV specific memory T cells were detected in the presence of these cells (1.3±0.4%) in comparison to Treg-depleted mice (2.6±0.9%) on d 30 after DNA immunization (n - 6, P<0.01). Both IFN-γ production and the avidity of the HBV-specific CD8+ T cell response to antigen were higher in HBV-specific CD8+ T cells induced in the absence of Treg cells. CONCLUSION: CD25+ Treg cells suppress priming and/or expansion of antigen-specific CD8+ T cells during DNA immunization and the peak CD8+ T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8+ T cell response and may affect the quality of memory T cell pools. The elimination of Treg cells or their inhibition may be important in immunotherapeutic strategies to control HBV infection by inducing virus-specific cytotoxic T lymphocyte responses in chronically infected subjects.
文摘The functional roles of memory B and T lymphocytes underlie the phenomenal success of prophylactic vaccinations, which have decreased morbidities and mortalities from infectious diseases globally over the last 50 years. However, it is becoming increasingly appreciated that memory cells are also capable of mediating the pathology associated with autoimmune disorders and transplant rejection, and may pose a significant barrier to future clinical advancement in immunoregulation. Therefore, understanding the unique properties of memory lymphocytes （as compared to their naive precursors） is a major area of investigation. Here, we focus on one of those singular properties of memory T cells （TM）-rapid recall. As will be discussed in more detail, rapid recall refers to the ability of quiescent TM cells to efficiently and robustly express‘effector functions＇ following stimulation. Studies that have advanced our understanding of TM cells＇ rapid recall using CD4^＋ T cells have been expertly reviewed elsewhere, so we will focus primarily on studies of CD8^＋ T cells. We will first review the different ways that CD8^＋ TM cells can be generated, followed by discussing how this influences their functional properties in the settings of immune protection and pathology. Then, rapid recall ability will be discussed, with emphasis placed on what is currently known about the mechanisms that underlie this unique property of TM cells.
基金the Deutsche Forschungsgemeinschaft (Emmy Noether Programm, SFB 610)the Wilhelm Sander Stiftung, and the Bundesministerium fuer Wissenschaft und Forschung (Start-up fonds Kompetenznetz Hepatitis)
文摘Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.
基金Supported by the Foundation of TCM Administration Bureau, Guangdong Province, No. 100115
文摘ABM: This study aims at exploring the distribution of TCM syndromes in CHB patients with HBV pre-core mutation (1896) and the relationship between pre-core mutation and T lymphocytes subgroup, through which to provide objective data on clinical syndrome differentiation of TCM, and further to suggest the therapeutic principle and guide clinical treatment. METHODS: One hundred and forty CHB patients were evenly divided into two study groups, HBV pre-core mutant group and HBV pre-core wild-type group. Besides, 30 healthy blood donors were selected as a healthy control group. HBV-labeled compound, T lymphocytes subgroup, and HBV-DNA pre-core mutant were tested in the study groups. T lymphocytes subgroup were also tested in the control group. All the patients were both diagnosed by syndrome differentiation of TCM and western medicine. RESULTS: The most common syndrome in mutant group was damp-heat combined with blood stasis, and the most common syndrome in the wild-type group was damp-heat stasis in the middle-jiao. There were more cases of medium and severe hepatitis in mutant group than that in wild-type group. The content of CD4+ lymphocytes and CD4+/CD8+ ratio were decreased gradually (healthy control group>wild-type group>mutant group). In the wild-type group, severe and medium CHB patients had considerably lower level of them than mild CHB patients. However, in the mutant group, the opposite result appeared. Meanwhile, the content of HBV-DNA in mutant group was higher than that in wild-type group. CONCLUSION: Damp, heat, toxin and blood stasis were the basic pathogens of CHB, whether pre-core mutant or not. CHB with precore mutant may lead to more severe hepatitis. The decreased content of CD4+ lymphocytes and ratio of CD4+/CD8+ may be taken as one of the indices in confirming the deficiency syndrome of CHB patients with pre-core mutation.
基金Supported by the Natural Science Foundation of China(No.30901906)the China Postdoctoral Science Foundation(No. 20080440743)
文摘OBJECTIVE: To evaluate the effect of Fuzhengpaidu granule (FZPDG) on immune activation molecules CD38 and human leukocyte antigen-D related (HLA-DR) on CD4+ and CD8+ cells in HIV/AIDS patients, and to explore the underlying mechanism of this therapy. METHODS: Plasma changes in CD3+, CD4+, CD8+, CD3+CD4+CD38+, CD3+CD4+HLA-DR+, CD3+ CD8+CD38+, and CD3+CD8+HLA-DR+levels in HIV/ AIDS patients treated with FZPDG for six months were examined by flow cytometry and compared with levels in healthy controls. RESULTS: The clinical trial included 34 outpatients with HIV/AIDS. Before treatment, plasma levels of CD38+ and HLA-DR+ on CD4/CD8 cells were higherthan those in 28 health controls (P<0.05). There were no significant changes in serum levels of CD3+, CD4+, and CD8+ T cells between pretreatment baseline versus after treatment, which were 82.85% ± 5.41% , 14.57% ± 10.31% and 54.55% ± 11.43% before treatment and 79.15% ± 8.21% , 19.96% ± 9.58% and 56.36% ± 11.67% after treatment, respectively (P>0.05). Plasma levels of CD3+ CD4+CD38+and CD3+CD4+HLA-DR+were 2.3%± 2.2% and 7.8%±5.5% before treatment and 1.2%± 0.8% and 2.6%±1.0% after treatment, respectively. Plasma levels of CD3+CD8+CD38+ and CD3+CD8+ HLA-DR+ were 41.4%±13.4% and 17.8%±11.3% beforetreatment,whichchangedto27.1%±10.2%and 3.8%±2.4%aftertreatment,respectively(P<0.05). CONCLUSION: HIV/AIDS patients exhibited an immune activation profile following FZPDG treatment. A potential mechanism of action for FZPDG appears to lie in its ability to up-regulate CD38 and HLA-DR levels on CD4+ T cells, and down-regulate them on CD8+ cells, thereby modulating immune activation of CD4+and CD8+T cells.
