目的评价OX40信号通路拮抗剂在治疗中重度特应性皮炎(AD)的安全性及有效性,为中重度AD治疗方案的选择提供参考依据。方法系统检索了PubMed、Web of Science、SinoMed和中国知网数据库,收集截至2024年2月发表的使用OX40信号通路拮抗剂,...目的评价OX40信号通路拮抗剂在治疗中重度特应性皮炎(AD)的安全性及有效性,为中重度AD治疗方案的选择提供参考依据。方法系统检索了PubMed、Web of Science、SinoMed和中国知网数据库,收集截至2024年2月发表的使用OX40信号通路拮抗剂,并以安慰剂作为对照的所有随机对照研究。对纳入的研究进行质量评价,使用RevMan5.3对结局指标进行Meta分析。最终共4篇文献907例中重度AD患者被纳入Meta分析。结果湿疹面积和严重程度指数(EASI)评分改善50%(RR:1.57,95%CI:1.29~1.92,P<0.0001)、75%(RR:2.11,95%CI:1.20~3.73,P=0.01)、90%及研究者整体评估(IGA)评分达0或1分(RR:4.10,95%CI:2.17~7.74,P<0.0001)的患者百分比均高于对照组,差异有统计学意义。试验组与对照组不良事件发生率比较差异无统计学意义(RR:1.05,95%CI:0.94~1.17,P=0.37);试验组停药率低于对照组,差异有统计学意义(RR:0.62,95%CI:0.47~0.82,P=0.001)。结论OX40信号通路拮抗剂在中重度AD的治疗中有良好的有效性及安全性,可能成为治疗AD的新选择。展开更多
Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that ...Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that the costimulatory molecules OX40 ligand(OX40L)and OX40 play essential roles in the immunological mechanisms of autoimmune diseases.Previously,we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells(PBMCs)of ITP patients.In our present study,OX40L-induced follicular helper T(Tfh)cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator(ICOS),programmed cell death protein-1(PD-1),and cluster of differentiation 40 ligand(CD40L)in vitro.Moreover,aberrant OX40L-OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo,inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model,which might accelerate the progression of ITP.Additionally,signal transduction through the OX40L-OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor(TRAF)-nuclear factor-κB(NF-κB)and Janus kinase(JAK)-signal transducer and activator of transcription(STAT)signaling pathways.Overall,OX40L-OX40 signaling is proposed as a potential novel therapeutic target for ITP.展开更多
目的研究外周血CD4^(+)CD28^(null)T细胞、肿瘤坏死因子受体超家族成员4(OX40)、4-1BB变化与糖尿病患者动脉粥样硬化(AS)进展的关联性。方法选取2型糖尿病(T2DM)患者120例,根据是否合并AS分为DM-AS组和DM组,比较两组外周血CD4^(+)CD28^(...目的研究外周血CD4^(+)CD28^(null)T细胞、肿瘤坏死因子受体超家族成员4(OX40)、4-1BB变化与糖尿病患者动脉粥样硬化(AS)进展的关联性。方法选取2型糖尿病(T2DM)患者120例,根据是否合并AS分为DM-AS组和DM组,比较两组外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率变化,并根据颈动脉狭窄程度分为轻度AS组(狭窄≤50%)、中度AS组(狭窄51%~69%)及重度AS组(狭窄≥70%),分析CD4^(+)CD28^(null)T细胞、OX40、4-1BB变化与AS进展的关联性。结果120例患者中,DM-AS组有76例,占63.33%;与DM组相比,DM-AS组的DM病程、收缩压、餐后2 h血糖(2 h PG)、糖化血红蛋白、载脂蛋白B、C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)水平及CD4^(+)CD28^(null)T细胞亚群比率、OX40阳性比率、4-1BB阳性比率较高,载脂蛋白A1水平较低,差异均有统计学意义(t分别=2.57、2.49、2.78、2.19、3.12、2.94、4.31、5.97、16.91、11.47、-2.52,P均<0.05);CD4^(+)CD28^(null)T细胞、OX40、4-1BB联合诊断DM-AS的曲线下面积(AUC)为0.96。DM-AS组76例中,其中轻度AS组37例、中度AS组29例、重度AS组10例。AS程度与CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均呈正相关(r分别=0.24、0.48、0.38,P均<0.05)。结论DM-AS患者的外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均明显升高,对DM-AS具有诊断价值,与AS进展呈正相关。展开更多
目的探讨共刺激分子OX40/OX40L在过敏性紫癜(HSP)患儿外周血单个核细胞(PBMC)中的表达及其在过敏性紫癜发病机制中的作用及临床意义。方法选取首次住院的34例HSP患儿作为观察组,另20例健康体检儿童作为对照组。采集分离PBMC,应用逆转录...目的探讨共刺激分子OX40/OX40L在过敏性紫癜(HSP)患儿外周血单个核细胞(PBMC)中的表达及其在过敏性紫癜发病机制中的作用及临床意义。方法选取首次住院的34例HSP患儿作为观察组,另20例健康体检儿童作为对照组。采集分离PBMC,应用逆转录-聚合酶链式反应(RT-PCR)检测OX40、OX40L mRNA的表达,并分析其与24 h尿微量白蛋白(24 h UMA)的相关性。结果 HSP患儿OX40、OX40L mRNA的表达均明显高于对照组,差异有统计学意义(P均<0.01)。24 h UMA增高的HSP患儿OX40、OX40L mRNA的表达均高于24 h UMA正常者,差异均有统计学意义(P均<0.05),且均与24 h UMA呈正相关(P<0.05)。结论过敏性紫癜患儿PBMC的OX40、OX40L mRNA表达有异常增高并与24 h UMA相关。提示OX40、OX40L可能参与了过敏性紫癜的发病,其或许可以作为监测HSP患儿病情及检测早期肾脏损害的免疫学指标。展开更多
Objectives:Currently,there exist two approaches to the treatment of malignant neoplasms:the Karanahan technology and in situ vaccination,which are based on chronometric delivery of therapeutic agents to the tumor depe...Objectives:Currently,there exist two approaches to the treatment of malignant neoplasms:the Karanahan technology and in situ vaccination,which are based on chronometric delivery of therapeutic agents to the tumor depending on the characteristics of tumor cells,as well as the immune status.The main purpose of this study was to experimentally prove the feasibility of combining the Karanahan technology and in situ vaccination withαOX40 antibodies into a single therapeutic platform to achieve a potent additive antitumor therapeutic effect.Methods:BALB/c mice grafted with B-cellular lymphoma A20 were treated using the Karanahan technology consisting of intraperitoneal cyclophosphamide administrations and intratumoral DNA injections according to an individually determined therapeutic regimen,together with in situ vaccination withαOX40.A pathomorphological analysis of the organs of experimental animals that died during the initial attempt to combine the two technologies was carried out.An analysis of blood cell populations was performed to determine the safe time for antibody administration:the number of immune cells capable of activating systemic inflammation(CD11b+Ly-6C+,CD11b+Ly-6G+,CD3–NKp46+CD11b+),the presence of Fc receptor and OX40 on the surface of these cells,and the number of neutrophils activated to NETosis were analyzed.Based on the analysis results,the antitumor efficacy of various modes of combining the Karanahan technology and in situ vaccination was studied.Results:WhenαOX40 was administered 5 h after each treatment using the Karanahan technology,mass death of mice caused by systemic inflammation and multiple organ failure was observed.The state of blood cells after the treatment using the Karanahan technology at the time points corresponding to antibody injections was analyzed to elucidate the reasons for this effect.It was found that at some time points,there occurs activation of the immune system and a powerful release(up to 16%)of monocytes and granulocytes carrying Fc receptor and OX40 on their surface into blood;when interacting withαOX40,they can activate the lytic potential of these cells.Activation of neutrophils to NETosis was also observed.Based on these findings,a study was carried out in different time regimes to combine the Karanahan technology andαOX40 injections.WhenαOX40 was injected into the points of minimal release of myeloid cells into the blood,increased survival rate and the greatest antitumor efficacy were observed:37%of animals survived without relapses on day 100 after experiment initiation.Conclusions:The results obtained indicate that it is possible to combine the Karanahan technology and in situ vaccination withαOX40,with obligatory constant monitoring of the number of myeloid cells in peripheral blood to determine the safe time for antibody injection.展开更多
文摘目的评价OX40信号通路拮抗剂在治疗中重度特应性皮炎(AD)的安全性及有效性,为中重度AD治疗方案的选择提供参考依据。方法系统检索了PubMed、Web of Science、SinoMed和中国知网数据库,收集截至2024年2月发表的使用OX40信号通路拮抗剂,并以安慰剂作为对照的所有随机对照研究。对纳入的研究进行质量评价,使用RevMan5.3对结局指标进行Meta分析。最终共4篇文献907例中重度AD患者被纳入Meta分析。结果湿疹面积和严重程度指数(EASI)评分改善50%(RR:1.57,95%CI:1.29~1.92,P<0.0001)、75%(RR:2.11,95%CI:1.20~3.73,P=0.01)、90%及研究者整体评估(IGA)评分达0或1分(RR:4.10,95%CI:2.17~7.74,P<0.0001)的患者百分比均高于对照组,差异有统计学意义。试验组与对照组不良事件发生率比较差异无统计学意义(RR:1.05,95%CI:0.94~1.17,P=0.37);试验组停药率低于对照组,差异有统计学意义(RR:0.62,95%CI:0.47~0.82,P=0.001)。结论OX40信号通路拮抗剂在中重度AD的治疗中有良好的有效性及安全性,可能成为治疗AD的新选择。
基金supported by the National Natural Science Foundation of China(Nos.82172335,81971994,91846103,and 81871709)the Zhejiang Provincial Key Research and Development Program(No.2020C03032),China.
文摘Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that the costimulatory molecules OX40 ligand(OX40L)and OX40 play essential roles in the immunological mechanisms of autoimmune diseases.Previously,we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells(PBMCs)of ITP patients.In our present study,OX40L-induced follicular helper T(Tfh)cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator(ICOS),programmed cell death protein-1(PD-1),and cluster of differentiation 40 ligand(CD40L)in vitro.Moreover,aberrant OX40L-OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo,inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model,which might accelerate the progression of ITP.Additionally,signal transduction through the OX40L-OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor(TRAF)-nuclear factor-κB(NF-κB)and Janus kinase(JAK)-signal transducer and activator of transcription(STAT)signaling pathways.Overall,OX40L-OX40 signaling is proposed as a potential novel therapeutic target for ITP.
文摘目的研究外周血CD4^(+)CD28^(null)T细胞、肿瘤坏死因子受体超家族成员4(OX40)、4-1BB变化与糖尿病患者动脉粥样硬化(AS)进展的关联性。方法选取2型糖尿病(T2DM)患者120例,根据是否合并AS分为DM-AS组和DM组,比较两组外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率变化,并根据颈动脉狭窄程度分为轻度AS组(狭窄≤50%)、中度AS组(狭窄51%~69%)及重度AS组(狭窄≥70%),分析CD4^(+)CD28^(null)T细胞、OX40、4-1BB变化与AS进展的关联性。结果120例患者中,DM-AS组有76例,占63.33%;与DM组相比,DM-AS组的DM病程、收缩压、餐后2 h血糖(2 h PG)、糖化血红蛋白、载脂蛋白B、C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)水平及CD4^(+)CD28^(null)T细胞亚群比率、OX40阳性比率、4-1BB阳性比率较高,载脂蛋白A1水平较低,差异均有统计学意义(t分别=2.57、2.49、2.78、2.19、3.12、2.94、4.31、5.97、16.91、11.47、-2.52,P均<0.05);CD4^(+)CD28^(null)T细胞、OX40、4-1BB联合诊断DM-AS的曲线下面积(AUC)为0.96。DM-AS组76例中,其中轻度AS组37例、中度AS组29例、重度AS组10例。AS程度与CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均呈正相关(r分别=0.24、0.48、0.38,P均<0.05)。结论DM-AS患者的外周血CD4^(+)CD28^(null)T细胞亚群比率及OX40、4-1BB阳性比率均明显升高,对DM-AS具有诊断价值,与AS进展呈正相关。
文摘目的探讨共刺激分子OX40/OX40L在过敏性紫癜(HSP)患儿外周血单个核细胞(PBMC)中的表达及其在过敏性紫癜发病机制中的作用及临床意义。方法选取首次住院的34例HSP患儿作为观察组,另20例健康体检儿童作为对照组。采集分离PBMC,应用逆转录-聚合酶链式反应(RT-PCR)检测OX40、OX40L mRNA的表达,并分析其与24 h尿微量白蛋白(24 h UMA)的相关性。结果 HSP患儿OX40、OX40L mRNA的表达均明显高于对照组,差异有统计学意义(P均<0.01)。24 h UMA增高的HSP患儿OX40、OX40L mRNA的表达均高于24 h UMA正常者,差异均有统计学意义(P均<0.05),且均与24 h UMA呈正相关(P<0.05)。结论过敏性紫癜患儿PBMC的OX40、OX40L mRNA表达有异常增高并与24 h UMA相关。提示OX40、OX40L可能参与了过敏性紫癜的发病,其或许可以作为监测HSP患儿病情及检测早期肾脏损害的免疫学指标。
基金supported by Inga N.Zaitseva“Karanahan”LLC and the Ministry of Science and Higher Education of the Russian Federation via the Institute of Cytology and Genetics(State Budget Project No.FWNR-2022-0016).
文摘Objectives:Currently,there exist two approaches to the treatment of malignant neoplasms:the Karanahan technology and in situ vaccination,which are based on chronometric delivery of therapeutic agents to the tumor depending on the characteristics of tumor cells,as well as the immune status.The main purpose of this study was to experimentally prove the feasibility of combining the Karanahan technology and in situ vaccination withαOX40 antibodies into a single therapeutic platform to achieve a potent additive antitumor therapeutic effect.Methods:BALB/c mice grafted with B-cellular lymphoma A20 were treated using the Karanahan technology consisting of intraperitoneal cyclophosphamide administrations and intratumoral DNA injections according to an individually determined therapeutic regimen,together with in situ vaccination withαOX40.A pathomorphological analysis of the organs of experimental animals that died during the initial attempt to combine the two technologies was carried out.An analysis of blood cell populations was performed to determine the safe time for antibody administration:the number of immune cells capable of activating systemic inflammation(CD11b+Ly-6C+,CD11b+Ly-6G+,CD3–NKp46+CD11b+),the presence of Fc receptor and OX40 on the surface of these cells,and the number of neutrophils activated to NETosis were analyzed.Based on the analysis results,the antitumor efficacy of various modes of combining the Karanahan technology and in situ vaccination was studied.Results:WhenαOX40 was administered 5 h after each treatment using the Karanahan technology,mass death of mice caused by systemic inflammation and multiple organ failure was observed.The state of blood cells after the treatment using the Karanahan technology at the time points corresponding to antibody injections was analyzed to elucidate the reasons for this effect.It was found that at some time points,there occurs activation of the immune system and a powerful release(up to 16%)of monocytes and granulocytes carrying Fc receptor and OX40 on their surface into blood;when interacting withαOX40,they can activate the lytic potential of these cells.Activation of neutrophils to NETosis was also observed.Based on these findings,a study was carried out in different time regimes to combine the Karanahan technology andαOX40 injections.WhenαOX40 was injected into the points of minimal release of myeloid cells into the blood,increased survival rate and the greatest antitumor efficacy were observed:37%of animals survived without relapses on day 100 after experiment initiation.Conclusions:The results obtained indicate that it is possible to combine the Karanahan technology and in situ vaccination withαOX40,with obligatory constant monitoring of the number of myeloid cells in peripheral blood to determine the safe time for antibody injection.
