Objective： To investigate the expression of CD40 and CD40 ligand （CD4OL） on the surface of peripheral blood mononuclear cells（PBMCs） in asthmatic rats and the effect of anti-CD40L McAb on cytokines of PBMCs. Meth...Objective： To investigate the expression of CD40 and CD40 ligand （CD4OL） on the surface of peripheral blood mononuclear cells（PBMCs） in asthmatic rats and the effect of anti-CD40L McAb on cytokines of PBMCs. Methods： Flow cytometry and RT-PCR were used to detect the expression of CD40 and CD40L of PBMCs in asthmatic rats. After the PBMCs was treated with anti-CD40L McAb, ELISA was used to detect the IL-4 and IFN-γ levels of culture supernatants. Results： Compared with the normal control group, the expression of CD40 and CD40L of PBMCs in asthmatic rats increased （P 〈 0.05）. Compared with the untreated group, the level of IL-γ and the ratio of IL-4/IFN-γ decreased after the PBMCs was treated with anti-CD40L McAb（P 〈 0.05）. Conclusion： The expression of CD40 and CD40L on the surface of PBMCs in asthmatic rats was up-regulated. Anti-CD40L McAb can rectify the imbalance of Th1 and Th2 cytokines.展开更多
Costimulatory signals are crucial for T cell activation. Attempts to block costimulatory pathways have been effective in preventing unwanted immune reactions. In particular, blocking the CD28/cytotoxic T lymphocyte an...Costimulatory signals are crucial for T cell activation. Attempts to block costimulatory pathways have been effective in preventing unwanted immune reactions. In particular, blocking the CD28/cytotoxic T lymphocyte antigen(CTLA)-4/B7 interaction(using CTLA-4Ig) and the CD40/CD40 L interaction(using anti-CD40 L antibodies) prevents T cell mediated autoimmune diseases, transplant rejection and graft vs host disease in experimental models. Moreover, CTLA-4Ig is in clinical use to treat rheumatoid arthritis(abatacept) and to prevent rejection of renal transplants(belatacept). Under certain experimental conditions, this treatment can even result in tolerance. Surprisingly, the underlying mechanisms of immune modulation are still not completely understood. We here discuss the evidence that costimulation blockade differentially affects effector T cells(Teff) and regulatory T cells(Treg). The latter are required to control inappropriate and unwanted immune responses, and their activity often contributes to tolerance induction and maintenance. Unfortunately, our knowledge on the costimulatory requirements of Treg cells is very limited. We therefore summarize the current understanding ofthe costimulatory requirements of Treg cells, and elaborate on the effect of anti-CD40 L antibody and CTLA-4Ig treatment on Treg cell activity. In this context, we point out that the outcome of a treatment aiming at blocking the CD28/CTLA-4/B7 costimulatory interaction can vary with dosing, timing and underlying immunopathology.展开更多
Hyper IgM syndrome is a rare immunodeficiency disease characterized by low or absent IgG, IgA, and IgE levels but normal or elevated level of IgM. It can occur as an acquired form or X linked or autosomal mode of in...Hyper IgM syndrome is a rare immunodeficiency disease characterized by low or absent IgG, IgA, and IgE levels but normal or elevated level of IgM. It can occur as an acquired form or X linked or autosomal mode of inheritance. The X linked form (HIGM1) is a result of mutations in the CD40L ligand (CD40L) gene. We investigate the expression of CD40L on activated T cells from a sporadic male case of HIM with no family history and the B cell function in response to anti CD40L mAb and cytokines. Staining of CD40L on activated T cells from the patient is negative with recently developed anti human CD40L mAb, M90 and M92. The low expression of CD40L on activated T cells from the patient′s mother is also detected. Sequencing of CD40L coding region reveals a 4 bp deletion within the CD40L binding domain. These results indicate that the patient has X linked inheritance pattern (XIGM1). CD40L mAb alone could induce the patient′s PBMCs to secret markedly IgG. Our data suggest that the detection of CD40L expression on ativated T cells may be used to identify sporadic cases of HIM as HIGM1.展开更多
CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vacci...CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.展开更多
文摘Objective： To investigate the expression of CD40 and CD40 ligand （CD4OL） on the surface of peripheral blood mononuclear cells（PBMCs） in asthmatic rats and the effect of anti-CD40L McAb on cytokines of PBMCs. Methods： Flow cytometry and RT-PCR were used to detect the expression of CD40 and CD40L of PBMCs in asthmatic rats. After the PBMCs was treated with anti-CD40L McAb, ELISA was used to detect the IL-4 and IFN-γ levels of culture supernatants. Results： Compared with the normal control group, the expression of CD40 and CD40L of PBMCs in asthmatic rats increased （P 〈 0.05）. Compared with the untreated group, the level of IL-γ and the ratio of IL-4/IFN-γ decreased after the PBMCs was treated with anti-CD40L McAb（P 〈 0.05）. Conclusion： The expression of CD40 and CD40L on the surface of PBMCs in asthmatic rats was up-regulated. Anti-CD40L McAb can rectify the imbalance of Th1 and Th2 cytokines.
文摘Costimulatory signals are crucial for T cell activation. Attempts to block costimulatory pathways have been effective in preventing unwanted immune reactions. In particular, blocking the CD28/cytotoxic T lymphocyte antigen(CTLA)-4/B7 interaction(using CTLA-4Ig) and the CD40/CD40 L interaction(using anti-CD40 L antibodies) prevents T cell mediated autoimmune diseases, transplant rejection and graft vs host disease in experimental models. Moreover, CTLA-4Ig is in clinical use to treat rheumatoid arthritis(abatacept) and to prevent rejection of renal transplants(belatacept). Under certain experimental conditions, this treatment can even result in tolerance. Surprisingly, the underlying mechanisms of immune modulation are still not completely understood. We here discuss the evidence that costimulation blockade differentially affects effector T cells(Teff) and regulatory T cells(Treg). The latter are required to control inappropriate and unwanted immune responses, and their activity often contributes to tolerance induction and maintenance. Unfortunately, our knowledge on the costimulatory requirements of Treg cells is very limited. We therefore summarize the current understanding ofthe costimulatory requirements of Treg cells, and elaborate on the effect of anti-CD40 L antibody and CTLA-4Ig treatment on Treg cell activity. In this context, we point out that the outcome of a treatment aiming at blocking the CD28/CTLA-4/B7 costimulatory interaction can vary with dosing, timing and underlying immunopathology.
文摘Hyper IgM syndrome is a rare immunodeficiency disease characterized by low or absent IgG, IgA, and IgE levels but normal or elevated level of IgM. It can occur as an acquired form or X linked or autosomal mode of inheritance. The X linked form (HIGM1) is a result of mutations in the CD40L ligand (CD40L) gene. We investigate the expression of CD40L on activated T cells from a sporadic male case of HIM with no family history and the B cell function in response to anti CD40L mAb and cytokines. Staining of CD40L on activated T cells from the patient is negative with recently developed anti human CD40L mAb, M90 and M92. The low expression of CD40L on activated T cells from the patient′s mother is also detected. Sequencing of CD40L coding region reveals a 4 bp deletion within the CD40L binding domain. These results indicate that the patient has X linked inheritance pattern (XIGM1). CD40L mAb alone could induce the patient′s PBMCs to secret markedly IgG. Our data suggest that the detection of CD40L expression on ativated T cells may be used to identify sporadic cases of HIM as HIGM1.
文摘CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.
