The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulate...The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.展开更多
Background The transcription factor, repressor of GATA-3 （ROG）, can simultaneously suppress the expression of T helper cells （Thl and Th2） cytokines. Since the suppression of Th2 cytokines by GATA-3 is well unders...Background The transcription factor, repressor of GATA-3 （ROG）, can simultaneously suppress the expression of T helper cells （Thl and Th2） cytokines. Since the suppression of Th2 cytokines by GATA-3 is well understood, it is postulated that there are other molecular targets of ROG that can suppress the expression of the Thl cytokines. We hypothesized that ROG might suppress the stimulators of T lymphocyte cytokines such as CD3, CD28, and inducible costimulator （ICOS）, or indirectly enhance the expression of cytokine suppressors such as T lymphocyte-associated antigen-4 （CTLA-4） and CD45. The objective of this study was to clarify the molecular targets of ROG involved in suppressing Thl or Th2 cytokines. Methods Real-time quantitative PCR （RT-PCR） and Western blotting were performed to evaluate the mRNA and protein levels of CD3, CD28, ICOS, CTLA-4, and CD45 in Thl and Th2 cells during various levels of ROG expression. Enzyme-linked immunosorbent assay （ELISA） was used to measure the levels of interferon-y （IFN-y） and intedeukin （IL）-4 in culture media of Thl and Th2 cells. Results The results showed that the mRNA and protein levels of ROG were relatively low in Thl and Th2 cells （P 〈0.01）. After ROG-pcDNA3.1 transfection, the mRNA and protein level of ROG was significantly elevated, while the expression of ICOS, IFN-y, and IL-4 was markedly down-regulated （P 〈0.01）. Conversely, transfection of ROG-siRNA led to inhibition of ROG expression and up-regulation of ICOS, IFN-y and IL-4 （P 〈0.01）. However, the expression levels of CD3, CD28, CTLA-4 and CD45 did not change in either ROG-pcDNA3.1 or ROG-siRNA-transfected Thl and Th2 cells （P 〉0.05）. Conclusion It is concluded that ROG can inhibit the expression of Thl and Th2 cytokines by down-regulating the expression of ICOS, which might be a potential molecular target for asthma treatment.展开更多
The main approach to reduce graft rejection has been focused on the development of immunosuppressive agents at present.Although these strategies have reportedly reduced graft rejection,there has been a reciprocal incr...The main approach to reduce graft rejection has been focused on the development of immunosuppressive agents at present.Although these strategies have reportedly reduced graft rejection,there has been a reciprocal increase in more severe immunosuppression and lethal infections,as well as severe side effects.Blockade of costimulatory T cell response has been proved as one of useful strategies to reduce graft rejection.Furthermore, it has been shown that infusion of dendritic cells(DCs)with a potent negative regulatory ability for T cells could prolong allograft survival.In this study mouse DCs(mDCs)were transfected with the recombinant plasmid pcDNA3.0 containing mouse inducible costimulator-Ig(mICOS-Ig) cDNA by electroporation.The transient expression of mICOS-Ig in mDC could be detected by ELISA and SDS-PAGE.Mouse ICOS-Ig fusion protein expressed in mDC and mICOS-Ig gene-modified mDC could inhibit lymphocyte proliferation in mixed lymphocyte culture(MLC)in vitro.Furthermore,mICOS-Ig gene-modified mDC could inhibit lymphocyte proliferation in recipient mice.These results suggested that mICOS-Ig gene-modified mDC exerted inhibitory effects on T cells,and might be suitable for treatment or prevention of graft rejection and immunopathologic diseases.Cellular & Molecular Immunology.2004;1(2):153-157.展开更多
文摘The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 30900660, No. 30871134 and No. 81172227） and Shanghai Committee of Science and Technology of China （No. 08JC1407600）. Conflict of interests： None.
文摘Background The transcription factor, repressor of GATA-3 （ROG）, can simultaneously suppress the expression of T helper cells （Thl and Th2） cytokines. Since the suppression of Th2 cytokines by GATA-3 is well understood, it is postulated that there are other molecular targets of ROG that can suppress the expression of the Thl cytokines. We hypothesized that ROG might suppress the stimulators of T lymphocyte cytokines such as CD3, CD28, and inducible costimulator （ICOS）, or indirectly enhance the expression of cytokine suppressors such as T lymphocyte-associated antigen-4 （CTLA-4） and CD45. The objective of this study was to clarify the molecular targets of ROG involved in suppressing Thl or Th2 cytokines. Methods Real-time quantitative PCR （RT-PCR） and Western blotting were performed to evaluate the mRNA and protein levels of CD3, CD28, ICOS, CTLA-4, and CD45 in Thl and Th2 cells during various levels of ROG expression. Enzyme-linked immunosorbent assay （ELISA） was used to measure the levels of interferon-y （IFN-y） and intedeukin （IL）-4 in culture media of Thl and Th2 cells. Results The results showed that the mRNA and protein levels of ROG were relatively low in Thl and Th2 cells （P 〈0.01）. After ROG-pcDNA3.1 transfection, the mRNA and protein level of ROG was significantly elevated, while the expression of ICOS, IFN-y, and IL-4 was markedly down-regulated （P 〈0.01）. Conversely, transfection of ROG-siRNA led to inhibition of ROG expression and up-regulation of ICOS, IFN-y and IL-4 （P 〈0.01）. However, the expression levels of CD3, CD28, CTLA-4 and CD45 did not change in either ROG-pcDNA3.1 or ROG-siRNA-transfected Thl and Th2 cells （P 〉0.05）. Conclusion It is concluded that ROG can inhibit the expression of Thl and Th2 cytokines by down-regulating the expression of ICOS, which might be a potential molecular target for asthma treatment.
基金surpported by National Key Basic Research Program of China(No.CB510008)
文摘The main approach to reduce graft rejection has been focused on the development of immunosuppressive agents at present.Although these strategies have reportedly reduced graft rejection,there has been a reciprocal increase in more severe immunosuppression and lethal infections,as well as severe side effects.Blockade of costimulatory T cell response has been proved as one of useful strategies to reduce graft rejection.Furthermore, it has been shown that infusion of dendritic cells(DCs)with a potent negative regulatory ability for T cells could prolong allograft survival.In this study mouse DCs(mDCs)were transfected with the recombinant plasmid pcDNA3.0 containing mouse inducible costimulator-Ig(mICOS-Ig) cDNA by electroporation.The transient expression of mICOS-Ig in mDC could be detected by ELISA and SDS-PAGE.Mouse ICOS-Ig fusion protein expressed in mDC and mICOS-Ig gene-modified mDC could inhibit lymphocyte proliferation in mixed lymphocyte culture(MLC)in vitro.Furthermore,mICOS-Ig gene-modified mDC could inhibit lymphocyte proliferation in recipient mice.These results suggested that mICOS-Ig gene-modified mDC exerted inhibitory effects on T cells,and might be suitable for treatment or prevention of graft rejection and immunopathologic diseases.Cellular & Molecular Immunology.2004;1(2):153-157.
