The balance between Th17 cells and regulatory T cells(Tregs)has emerged as a prominent factor in regulating autoimmunity and cancer.Th17 cells are vital for host defense against pathogens but have also been implicated...The balance between Th17 cells and regulatory T cells(Tregs)has emerged as a prominent factor in regulating autoimmunity and cancer.Th17 cells are vital for host defense against pathogens but have also been implicated in causing autoimmune disorders and cancer,though their role in carcinogenesis is less well understood.Tregs are required for self-tolerance and defense against autoimmunity and often correlate with cancer progression.This review addresses the importance of a functional homeostasis between these two subsets in health and the consequences of its disruption when these forces collide in disease.Importantly,we discuss the ability of Th17 cells to mediate cancer regression in immunotherapy,including adoptive transfer and checkpoint blockade therapy,and the therapeutic possibilities of purposefully offsetting the Th17/Treg balance to treat patients with cancer as well as those with autoimmune diseases.展开更多
AIM: To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACHBLF) and to...AIM: To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACHBLF) and to analyze changes in Th17 and Treg phenotypes during disease progression.展开更多
FOXP3＋ regulatory T （Treg） cells are critical in maintaining immune tolerance and homeostasis of the immune system. The molecular mechanisms underlying the stability, plasticity and functional activity of Treg cell...FOXP3＋ regulatory T （Treg） cells are critical in maintaining immune tolerance and homeostasis of the immune system. The molecular mechanisms underlying the stability, plasticity and functional activity of Treg cells have been much studied in recent years. Here, we summarize these intriguing findings, and provide insight into their potential use or manipulation during Treg cell therapy for the treatment of autoimmune diseases, graft-versus-host disease （GVHD） and cancer.展开更多
CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcription...CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs,but recent studies have revealed increasing complexities for CD4^(+)T-cell differentiation.Here,we first discuss CD4^(+)T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells.We next describe the mechanisms underlying CD4^(+)T-cell differentiation,including cytokine-induced signaling and transcriptional networks.We then review current and emerging topics of differentiation,including the plasticity and heterogeneity of T cells,the tissue-specific effects,and the influence of cellular metabolism on cell fate decisions.Importantly,recent advances in cutting-edge approaches,especially systems biology tools,have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.展开更多
AIM: To investigate the role of T helper 17 cells (Th17) and regulatory T cells (Treg) in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF).METHODS: We enrolled 79 patients with HBV infection into ...AIM: To investigate the role of T helper 17 cells (Th17) and regulatory T cells (Treg) in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF).METHODS: We enrolled 79 patients with HBV infection into the study, 50 patients with HBV-related ACLF and 29 patients with chronic hepatitis B (CHB), from the First Affiliated Hospital of Medical College from January 2009 to June 2012. The ACLF patients were diagnosed according to the criteria recommended by The 19th Conference of the Asian Pacific Association for the Study of the Liver in 2009. Twenty healthy individuals with a similar gender and age structures to the two patient groups were also included as the normal controls (NC). Of the 50 ACLF patients, 28 were subsequently classified as non-survivors: 19 patients died from multiorgan failure, 3 underwent liver transplantation, and 6 discontinued therapy during follow-up because of financial reasons. The remaining 22 ACLF patients whose liver and anticoagulation function recovered to nearly normal levels within the next 6 mo were classified as survivors. The number of circulating Treg and Th17 cells was determined upon diagnosis and during the 8th week of follow-up through flow cytometry. RESULTS: The percentage of circulating Treg cells in the ACLF group was significantly higher than that in the CHB group (5.50% ± 1.15% vs 3.30% ± 1.13%, P < 0.01). The percentages of circulating Th17 cells in the ACLF and the CHB groups were significantly higher than that in the NC group (6.32% ± 2.22% vs 1.56% ± 0.44%, P < 0.01; 3.53% ± 1.65% vs 1.56% ± 0.44%, P < 0.01). No significant difference in Treg cell to Th17 cell ratio was observed between the ACLF group and the CHB group (0.98 ± 0.44 vs 1.12 ± 0.64, P = 0.991), whereas those in the two HBV infection groups were significantly lower than that in the NC group (1.85 ± 1.22; both P < 0.01). The percentage of Treg cells in the survivors during the 8th week of follow-up was significantly lower than that during peak ACLF severity [total bilirubin (TBIL) 展开更多
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 immunot展开更多
AIM: To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms. METHODS: The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided...AIM: To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms. METHODS: The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided into four groups: normal control, UC model group, resveratrol low-dose group (RLD; 50 mg/kg per day), and resveratrol high-dose group (RHD; 100 mg/kg per day). RESULTS: The results showed that RLD regulates Treg/Th17 balance mainly through reducing the number of Th17 cells, whereas RHD regulates Treg/Th17 balance through both downregulating the number of Th17 cells and upregulating the number of Treg cells. Resveratrol can also regulate the level of plasma and intestinal mucosal cytokines including interleukin (IL)-10, transforming growth factor-beta 1, IL-6, and IL-17. The expressions of hypoxia inducible factor (HIF)-1 alpha, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 were significantly decreased in the intestinal tissues of mice treated with resveratrol. CONCLUSION: The therapeutic efficacy of resveratrol in UC is dose dependent and closely associated with the regulation of Treg/Th17 balance and the HIF-1 alpha/mTOR signaling pathway.展开更多
The T cell co-stimulatory molecule OX40 and its cognate ligand OX40 L have attracted broad research interest as a therapeutic target in T cell-mediated diseases.Accumulating preclinical evidence highlights the therape...The T cell co-stimulatory molecule OX40 and its cognate ligand OX40 L have attracted broad research interest as a therapeutic target in T cell-mediated diseases.Accumulating preclinical evidence highlights the therapeutic efficacy of both agonist and blockade of the OX40-OX40 L interaction.Despite this progress,many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered.In this review we summarize the impact of the OX40-OX40 L interaction on T cell subsets,including Th1,Th2,Th9,Th17,Th22,Treg,Tfh,and CD8+T cells,to gain a comprehensive understanding of anti-OX40 mAb-based therapies.The potential therapeutic application of the OX40-OX40 L interaction in autoimmunity diseases and cancer immunotherapy are further discussed;OX40-OX40 L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases.We also explore the rationale of targeting OX40-OX40 L interactions in cancer immunotherapy.Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells.When combined with other therapeutic treatments,such as anti-PD-1 or anti-CTLA-4 blockade,cytokines,chemotherapy,or radiotherapy,the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced.These data collectively suggest great potential for OX40-mediated therapies.展开更多
目的研究薏苡仁酯对胶原诱导性关节炎(collagen induced arthritis,CIA)小鼠外周血中Foxp3+CD4+CD25+调节性T细胞(Treg)的影响,探讨薏苡仁酯类风湿关节炎治疗中的可能机制。方法从25只小鼠随机选取5只为正常组,剩余20只小鼠进行CIA造模...目的研究薏苡仁酯对胶原诱导性关节炎(collagen induced arthritis,CIA)小鼠外周血中Foxp3+CD4+CD25+调节性T细胞(Treg)的影响,探讨薏苡仁酯类风湿关节炎治疗中的可能机制。方法从25只小鼠随机选取5只为正常组,剩余20只小鼠进行CIA造模。造模成功后随机分为造模对照组10只及薏苡仁酯组10只。薏苡仁酯组予薏苡仁酯注射液25 m L/kg,正常组及造模对照组注射生理盐水25 m L/kg,均每天腹腔内注射1次。共用药21天。用药后对各组关节炎进行评分,计算关节炎指数,并应用流式细胞术测定小鼠外周血Foxp3+CD4+CD25+Treg比例。结果与正常组比较,造模对照组关节炎指数明显升高(P<0.01),薏苡仁酯组较造模对照组小鼠关节炎指数明显下降(P<0.01)。与正常组比较,造模对照组Foxp3+CD4+CD25+Treg水平均明显下降(P<0.01),薏苡仁酯组较造模对照组用药后Foxp3+CD4+CD25+Treg水平明显升高,差异有统计学意义(P<0.01)。结论薏苡仁酯能上调CIA小鼠Foxp3+CD4+CD25+Treg比例,可能在CIA的发病中具有一定的免疫调节作用。展开更多
The programmed cell death-1(PD-1)/PD-ligand 1(PD-L1)pathway is critical for normal pregnancy by promoting regulatory T(Treg)cell development and inhibiting the Th17 response.However,the relationship between the PD-1/P...The programmed cell death-1(PD-1)/PD-ligand 1(PD-L1)pathway is critical for normal pregnancy by promoting regulatory T(Treg)cell development and inhibiting the Th17 response.However,the relationship between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance in pre-eclampsia(PE)is an enigma.In this study,decreased PD-1 and PD-L1 expression and a Treg/Th17 imbalance were observed at the maternal-fetal interface in PE.The regulatory effects of the PD-1/PD-L1 pathway on the Treg and Th17 cell quantities were determined in vitro by targeting T-cell proliferation,differentiation and transdifferentiation.First,decreased PD-1 expression might contribute to a higher Th17 cell frequency by promoting proliferation in PE.Second,the percentages of Treg but not Th17 cells differentiated from peripheral naive CD4+T cells were increased by PD-L1 Fc administration.This effect was accompanied by decreased PI3K/AKT/m-TOR and increased PTEN mRNA expression and was completely reversed by PD-1 blockade.Finally,the percentage of IL-17-producing Treg cells increased and was positively associated with the Th17 cell frequency in PE.Increased RORγt and IL-17 but not Foxp3 and IL-10 mRNA expression by Treg cells was observed with PD-1 blockade.Similar findings occurred when Treg cells were exposed to IL-6/IL-23/IL-1βand were reversed by PD-L1 Fc.Taken together,our findings indicate that the PD-1/PD-L1 pathway contributes to the Treg/Th17 imbalance via‘one-two punch’approaches:(i)promoting Th17 cell proliferation,(ii)inhibiting Treg cell differentiation and(iii)enhancing Treg cell plasticity into Th17 cells in PE.The therapeutic value of PD-L1 Fc for PE treatment will be explored in the future.展开更多
基金supported in part by NIH Training grant T32 GM08716 to H.M.K.,NIH Fellowship grant F31 CA192787 to S.R.B.,NIH Training grant T32 AI132164-01 to C.J.D.,NCI Grants R01 CA175061 and R01 CA208514,KL2 South Carolina Clinical&Translational Research grant UL1 TR000062,ACS-IRG grant 016623-004 and MUSC Start-up funds to C.M.P.
文摘The balance between Th17 cells and regulatory T cells(Tregs)has emerged as a prominent factor in regulating autoimmunity and cancer.Th17 cells are vital for host defense against pathogens but have also been implicated in causing autoimmune disorders and cancer,though their role in carcinogenesis is less well understood.Tregs are required for self-tolerance and defense against autoimmunity and often correlate with cancer progression.This review addresses the importance of a functional homeostasis between these two subsets in health and the consequences of its disruption when these forces collide in disease.Importantly,we discuss the ability of Th17 cells to mediate cancer regression in immunotherapy,including adoptive transfer and checkpoint blockade therapy,and the therapeutic possibilities of purposefully offsetting the Th17/Treg balance to treat patients with cancer as well as those with autoimmune diseases.
基金Supported by Grants from Shanghai Natural Science Fund,No.09ZR1400500National Natural Science Foundation of China No.30972600Shanghai Health Bureau Fund,No.2012092
文摘AIM: To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACHBLF) and to analyze changes in Th17 and Treg phenotypes during disease progression.
文摘FOXP3＋ regulatory T （Treg） cells are critical in maintaining immune tolerance and homeostasis of the immune system. The molecular mechanisms underlying the stability, plasticity and functional activity of Treg cells have been much studied in recent years. Here, we summarize these intriguing findings, and provide insight into their potential use or manipulation during Treg cell therapy for the treatment of autoimmune diseases, graft-versus-host disease （GVHD） and cancer.
基金the National Institutes of Health and the National Multiple Sclerosis Society.
文摘CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs,but recent studies have revealed increasing complexities for CD4^(+)T-cell differentiation.Here,we first discuss CD4^(+)T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells.We next describe the mechanisms underlying CD4^(+)T-cell differentiation,including cytokine-induced signaling and transcriptional networks.We then review current and emerging topics of differentiation,including the plasticity and heterogeneity of T cells,the tissue-specific effects,and the influence of cellular metabolism on cell fate decisions.Importantly,recent advances in cutting-edge approaches,especially systems biology tools,have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.
基金Supported by The Major National Science and Technology Projects for Infectious Diseases (11th and 12th Five Year, China),No. 2008ZX10002-007, No. 2012ZX10002-007the Foundation of Shaanxi Provincial Science and Technology Plan Projects,No. 2011K14-09-09
文摘AIM: To investigate the role of T helper 17 cells (Th17) and regulatory T cells (Treg) in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF).METHODS: We enrolled 79 patients with HBV infection into the study, 50 patients with HBV-related ACLF and 29 patients with chronic hepatitis B (CHB), from the First Affiliated Hospital of Medical College from January 2009 to June 2012. The ACLF patients were diagnosed according to the criteria recommended by The 19th Conference of the Asian Pacific Association for the Study of the Liver in 2009. Twenty healthy individuals with a similar gender and age structures to the two patient groups were also included as the normal controls (NC). Of the 50 ACLF patients, 28 were subsequently classified as non-survivors: 19 patients died from multiorgan failure, 3 underwent liver transplantation, and 6 discontinued therapy during follow-up because of financial reasons. The remaining 22 ACLF patients whose liver and anticoagulation function recovered to nearly normal levels within the next 6 mo were classified as survivors. The number of circulating Treg and Th17 cells was determined upon diagnosis and during the 8th week of follow-up through flow cytometry. RESULTS: The percentage of circulating Treg cells in the ACLF group was significantly higher than that in the CHB group (5.50% ± 1.15% vs 3.30% ± 1.13%, P < 0.01). The percentages of circulating Th17 cells in the ACLF and the CHB groups were significantly higher than that in the NC group (6.32% ± 2.22% vs 1.56% ± 0.44%, P < 0.01; 3.53% ± 1.65% vs 1.56% ± 0.44%, P < 0.01). No significant difference in Treg cell to Th17 cell ratio was observed between the ACLF group and the CHB group (0.98 ± 0.44 vs 1.12 ± 0.64, P = 0.991), whereas those in the two HBV infection groups were significantly lower than that in the NC group (1.85 ± 1.22; both P < 0.01). The percentage of Treg cells in the survivors during the 8th week of follow-up was significantly lower than that during peak ACLF severity [total bilirubin (TBIL)
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 immunot
文摘目的探究自拟二小汤(小青龙汤合小柴胡汤)治疗肺气虚寒型变应性鼻炎患者疗效及其对调节性T细胞(regulatory cells,Tregs)相关因子的作用。方法将64例患者随机分为观察组、对照组各32例。观察组应用自拟二小汤治疗,对照组采用氯雷他定片治疗。治疗28 d后,观察两组症状评分、血清中转化生长因子-β(transforming growth factor-β,TGF-β)、白介素10(interleukin-10,IL-10)、白细胞介素17(interleukin 17,IL-17)含量以及生活质量。结果治疗后,观察组的打喷嚏、鼻痒、鼻塞症状评分低于对照组(P<0.05);观察组血清中TGF-β、IL-10高于对照组(P<0.05),IL-17低于对照组(P<0.05);观察组鼻结膜炎生存量表(rhinoconjunctivitis quality of life scale,RQLQ评分)优于对照组(P<0.05)。结论自拟二小汤可以改善变应性鼻炎临床症状,提升患者血清中TGF-β、IL-10的含量,降低IL-17的含量,明显改善患者生活质量,效果全面优于氯雷他定片,值得临床进一步研究其机理及远期疗效。
基金Supported by Outstanding Doctoral Thesis Support Project of Guangdong Province,No.85514045the Technical Research and Development Project of Shenzhen,No.JCYJ20130402092657774the Medical Research Foundation of Guangdong Province,No.B2013347
文摘AIM: To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms. METHODS: The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided into four groups: normal control, UC model group, resveratrol low-dose group (RLD; 50 mg/kg per day), and resveratrol high-dose group (RHD; 100 mg/kg per day). RESULTS: The results showed that RLD regulates Treg/Th17 balance mainly through reducing the number of Th17 cells, whereas RHD regulates Treg/Th17 balance through both downregulating the number of Th17 cells and upregulating the number of Treg cells. Resveratrol can also regulate the level of plasma and intestinal mucosal cytokines including interleukin (IL)-10, transforming growth factor-beta 1, IL-6, and IL-17. The expressions of hypoxia inducible factor (HIF)-1 alpha, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 were significantly decreased in the intestinal tissues of mice treated with resveratrol. CONCLUSION: The therapeutic efficacy of resveratrol in UC is dose dependent and closely associated with the regulation of Treg/Th17 balance and the HIF-1 alpha/mTOR signaling pathway.
基金supported by the National Mitural Science Foundation of China(Nos.81872824 and 81690261).
文摘The T cell co-stimulatory molecule OX40 and its cognate ligand OX40 L have attracted broad research interest as a therapeutic target in T cell-mediated diseases.Accumulating preclinical evidence highlights the therapeutic efficacy of both agonist and blockade of the OX40-OX40 L interaction.Despite this progress,many questions about the immuno-modulator roles of OX40 on T cell function remain unanswered.In this review we summarize the impact of the OX40-OX40 L interaction on T cell subsets,including Th1,Th2,Th9,Th17,Th22,Treg,Tfh,and CD8+T cells,to gain a comprehensive understanding of anti-OX40 mAb-based therapies.The potential therapeutic application of the OX40-OX40 L interaction in autoimmunity diseases and cancer immunotherapy are further discussed;OX40-OX40 L blockade may ameliorate autoantigen-specific T cell responses and reduce immune activity in autoimmunity diseases.We also explore the rationale of targeting OX40-OX40 L interactions in cancer immunotherapy.Ligation of OX40 with targeted agonist anti-OX40 mAbs conveys activating signals to T cells.When combined with other therapeutic treatments,such as anti-PD-1 or anti-CTLA-4 blockade,cytokines,chemotherapy,or radiotherapy,the anti-tumor activity of agonist anti-OX40 treatment will be further enhanced.These data collectively suggest great potential for OX40-mediated therapies.
文摘目的研究薏苡仁酯对胶原诱导性关节炎(collagen induced arthritis,CIA)小鼠外周血中Foxp3+CD4+CD25+调节性T细胞(Treg)的影响,探讨薏苡仁酯类风湿关节炎治疗中的可能机制。方法从25只小鼠随机选取5只为正常组,剩余20只小鼠进行CIA造模。造模成功后随机分为造模对照组10只及薏苡仁酯组10只。薏苡仁酯组予薏苡仁酯注射液25 m L/kg,正常组及造模对照组注射生理盐水25 m L/kg,均每天腹腔内注射1次。共用药21天。用药后对各组关节炎进行评分,计算关节炎指数,并应用流式细胞术测定小鼠外周血Foxp3+CD4+CD25+Treg比例。结果与正常组比较,造模对照组关节炎指数明显升高(P<0.01),薏苡仁酯组较造模对照组小鼠关节炎指数明显下降(P<0.01)。与正常组比较,造模对照组Foxp3+CD4+CD25+Treg水平均明显下降(P<0.01),薏苡仁酯组较造模对照组用药后Foxp3+CD4+CD25+Treg水平明显升高,差异有统计学意义(P<0.01)。结论薏苡仁酯能上调CIA小鼠Foxp3+CD4+CD25+Treg比例,可能在CIA的发病中具有一定的免疫调节作用。
基金This study was supported by research grants from the National Natural Science Foundation of China(NO.81471475).
文摘The programmed cell death-1(PD-1)/PD-ligand 1(PD-L1)pathway is critical for normal pregnancy by promoting regulatory T(Treg)cell development and inhibiting the Th17 response.However,the relationship between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance in pre-eclampsia(PE)is an enigma.In this study,decreased PD-1 and PD-L1 expression and a Treg/Th17 imbalance were observed at the maternal-fetal interface in PE.The regulatory effects of the PD-1/PD-L1 pathway on the Treg and Th17 cell quantities were determined in vitro by targeting T-cell proliferation,differentiation and transdifferentiation.First,decreased PD-1 expression might contribute to a higher Th17 cell frequency by promoting proliferation in PE.Second,the percentages of Treg but not Th17 cells differentiated from peripheral naive CD4+T cells were increased by PD-L1 Fc administration.This effect was accompanied by decreased PI3K/AKT/m-TOR and increased PTEN mRNA expression and was completely reversed by PD-1 blockade.Finally,the percentage of IL-17-producing Treg cells increased and was positively associated with the Th17 cell frequency in PE.Increased RORγt and IL-17 but not Foxp3 and IL-10 mRNA expression by Treg cells was observed with PD-1 blockade.Similar findings occurred when Treg cells were exposed to IL-6/IL-23/IL-1βand were reversed by PD-L1 Fc.Taken together,our findings indicate that the PD-1/PD-L1 pathway contributes to the Treg/Th17 imbalance via‘one-two punch’approaches:(i)promoting Th17 cell proliferation,(ii)inhibiting Treg cell differentiation and(iii)enhancing Treg cell plasticity into Th17 cells in PE.The therapeutic value of PD-L1 Fc for PE treatment will be explored in the future.
