PD-1/PD-L信号通路在肝病研究中的进展

B7/CD28家族分子在调节T细胞活化及耐受方面起着重要作用。程序性死亡-1(programmed death1,PD-1)及其配体PD-L1(B7-H1)/PD-L2(B7-DC)是继CTLA24/CD28后发现的B7/CD28家族分子,具有诱导和维持外周耐受的双重作用,参与了病毒感染免疫、肿瘤免疫和自身免疫性疾病等。此文就PD-1及其配体的生物学特性及在肝病中的研究近况进行综述。     

PD-1/PD-L1在肝细胞癌中免疫调节作用的研究进展

肝细胞癌是世界上最常见的致死性肿瘤之一,程序性死亡蛋白-1(PD-1)和程序性死亡配体-1(PD-L1)这对免疫共抑制分子在肝癌细胞中广泛表达。目前以抗PD-1/PD-L1为靶点的免疫治疗在多种肿瘤中取得了良好而持久的疗效。然而PD-1/PD-L1在肝细胞癌微环境中的免疫调节机制尚待完善,是否对抗PD-1/PD-L1治疗敏感及如何联合其他治疗目前尚无定论。笔者主要对PD-1/PD-L1通路在肝细胞癌中的免疫调节及抗PD-1/PD-L1在肝细胞癌治疗方面的研究进展进行综述。     

PD-L1和PD-1在胃癌组织中的表达及其临床意义

目的：：探究在胃癌组织中PD-L1和PD-1表达情况及其临床应用意义。方法：2013年1月至2015年6月期间,我院接受根治手术治疗的胃癌患者80例手术区标本作为观察组,选取患者的癌旁组织标本作为对照组,对比患者的临床指标情况。结果：观察组标本的PD-L1和PD-1指标的阳性率分别为62.5％（50/80）、38.8％（31/80）,对照组组织的PD-L1和PD-1指标的阳性率均为0,两个指标表达情况没有相关性,其中PD-L1指标与患者的浸润情况、淋巴结转移情况以及pTNM分期情况密切相关,而PD-1表达与该类指标不相关。结论：在胃癌组织中PD-L1和PD-1指标有明显的升高,并且PD-L1指标与肿瘤的进展以及预后情况密切相关,值得在胃癌诊治中指导应用。     

PD-1/PD-L1在非小细胞肺癌中表达的生物学作用及临床意义

目的研究PD-1/PD-L1及EGFR在非小细胞肺癌中的表达和相关性。方法收集我院96例非小细胞肺癌患者的病理标本和临床资料,使用免疫组化检测PD-1/PD-L1的表达情况,PCR检测EGFR的表达情况。使用Logistic回归分析评价PD-1/PD-L1和EGFR的相关性。结果吸烟患者的PD-1阳性率为76.7%(23例),显著高于不吸烟患者的21.2%(14例)(P<0.05)。女性患者的PD-L1阳性率为82.0%(41例),显著高于男性的45.7%(21例)(P<0.05)。腺癌患者的PD-L1阳性率为78.3%(47例),显著高于鳞癌的41.7%(15例)(P<0.05)。EGFR突变型患者的PD-L1阳性率为91.9%(34例),显著高于野生型的47.5%(28例)(P<0.05)。结论 PD-1在吸烟患者中高表达;PD-L1与EGFR呈正相关,且在女性、腺癌患者中高表达,PD-L1与EGFR基因表达的关系可能为个体化免疫治疗联合靶向治疗提供新的依据。     

肾透明细胞癌中PD-1和PD-L1的检测及临床意义

目的 检测程序性细胞死亡受体1(PD-1)及其配体程序性细胞死亡配体1(PD-L1)在肾透明细胞癌中的表达,并探讨两者的临床病理特征.方法 收集90例肾透明细胞癌组织蜡块为实验组,10例正常肾组织蜡块为对照组.采用免疫组化检测实验组中90例肾透明细胞癌组织和对照组中10例正常肾组织的PD-1和PD-L1表达情况.结果 ...     

PD-1/PD-L1与脓毒症的免疫紊乱

脓毒症(sepsis)在1991年初次被定义为感染所致的机体全身炎症反应综合征(SIRS).2016年脓毒症国际共识更新至Sepsis 3.0,即由感染所致宿主免疫反应失调引起的威胁生命的器官功能障碍.在脓毒症免疫抑制阶段,程序性死亡受体1(programmed cell death protein-1,PD-1)与程...     

矽尘对小鼠外周血免疫相关基因PD-1和PD-L1 mRNA表达的影响

将40只昆明种小鼠随机分为染尘2 h、4 h、8 h组以及对照组,共染尘30 d。染尘结束后,立即称量小鼠体重及肺脏、胸腺、脾脏重量,计算各脏器系数。提取外周血总RNA,RT-q PCR法检测各组小鼠外周血免疫相关基因PD-1和PD-L1 mRNA的相对含量。结果显示,与对照组比较,各染尘时间组小鼠体重增长速度减慢,肺脏系数升高,胸腺系数和脾脏系数降低(P均0.05),PD-L1 mRNA相对含量均升高(P0.05),4 h和8 h染尘组PD-1 mRNA相对含量升高(P0.05)。提示矽尘可导致小鼠免疫力损伤,该损伤可能与矽尘上调外周血PD-1和PD-L1 mRNA表达有关。     

利妥昔单抗联合CHOP化疗方案对弥漫性大B细胞淋巴瘤患者PD-1,PD-L1,T细胞亚群及NK细胞的影响

目的探讨利妥昔单抗联合CHOP(R-CHOP)化疗方案对弥漫性大B细胞淋巴瘤(DLBCL)患者PD-1,PD-L1,T细胞亚群及自然杀伤(NK)细胞的影响。方法选取2018年6月-2019年6月于辽宁省某医院就诊的80例DLBCL患者为研究对象,采用随机数字表法分为对照组与观察组,每组40例。对照组患者采用常规的CHOP化疗方案,观察组患者采用R-CHOP化疗方案,比较2组患者的临床疗效、程序性死亡因子-1(PD-1)与程序性死亡因子受体(PD-L1)阳性状况、T细胞亚群及NK细胞水平、不良反应发生情况。结果观察组患者治疗总有效率为95.0%,高于对照组的80.0%,差异有统计学意义(P0.05)。观察组患者PD-1阳性率为47.5%,低于对照组的70.0%,差异有统计学意义(P0.05);观察组患者PD-L1阳性率为50.0%,低于对照组的72.5%,差异有统计学意义(P0.05)。治疗前,2组患者CD3~+,CD4~+,CD8~+,CD4~+/CD8~+,NK细胞水平比较,差异均无统计学意义(P0.05);治疗后,2组患者CD3~+,CD4~+,CD8~+,CD4~+/CD8~+,NK细胞水平均高于治疗前,且观察组高于对照组,差异均有统计学意义(P0.05)。结论 R-CHOP化疗方案治疗DLBCL效果显著,可有效改善患者PD-1,PD-L1阳性状况及T细胞亚群与NK细胞水平,值得临床推广使用。     

PD-1/PD-L1在三阴型乳腺癌中的研究进展

程序性死亡受体-1(programmed cell death-1,PD-1)及其配体程序性死亡配体-1(programmed cell death ligand-1,PD-L1)共同组成PD-1/PD-L1免疫抑制信号通路,使恶性肿瘤发生免疫逃逸,现今以PD-L1/PD-L1为靶点的免疫治疗在许多恶性肿瘤的治疗中取得了突破性的进展。三阴型乳腺癌(triple-negative breast cancer,TNBC)是ER、PR和Her-2表达均为阴性的乳腺癌,其恶性程度高,且内分泌治疗及抗Her-2治疗无效,预后差,现有研究已经发现PD-1/PD-L1蛋白在TNBC中存在表达且部分临床试验显示PD-1/PD-L1抑制剂在TNBC的治疗中存在一定疗效,为TNBC的免疫治疗提供了一定可能性,现就PD-1/PD-L1在TNBC中的研究进展进行综述。     

EB病毒相关性胃癌PD-1和PD-L1信号通路表达水平及意义

目的 探讨程序性细胞死亡蛋白-1(PD-1)、程序性细胞死亡蛋白-1配体(PD-L1)信号通路在EB病毒(EBV)相关性胃癌患者胃癌组织的表达。方法 回顾性分析2017年6月-2021年6月在诸暨市中心医院消化内科就诊的190例胃癌患者,采用EB病毒编码的RNA(EBER)原位杂交法检测胃癌患者病理石蜡包埋组织中EBV表达情况,采用免疫组织化学链霉菌抗生物素蛋白-过氧化物酶连结(SP)法检测PD-1、PD-L1在胃癌组织中的表达。结果 190例胃癌患者组织切片经EBER原位杂交方法检测出EBV阳性19例,阳性率为10.00%。肿瘤部位、浸润深度与EBV感染具有相关性(P<0.05)。190例胃癌组织中PD-1信号通路表达阳性例数为79例,阳性率为41.58%; PD-L1信号通路表达阳性例数为29例,阳性率为15.26%。EBV相关性胃癌与非EBV相关性胃癌患者胃癌组织中PD-1及PD-L1信号通路阳性表达率比较差异有统计学意义(P<0.05)。结论 PD-1、PD-L1信号通路在EBV相关性胃癌中有较高的表达,对于近端胃及浸润深度较高的EBV感染高危胃癌患者,通过免疫检查...     

PD-1/PD-L1 blockade restores tumor-induced COVID-19 vaccine bluntness

The COVID-19 vaccinations are crucial in protecting against the global pandemic. However, accumulating studies revealed the severely blunted COVID-19 vaccine effectiveness in cancer patients. The PD-1/PD-L1 immune checkpoint blockade (ICB) therapy leads to durable therapeutic responses in a subset of cancer patients and has been approved to treat a wide spectrum of cancers in the clinic. In this regard, it is pivotal to explore the potential impact of PD-1/PD-L1 ICB therapy on COVID-19 vaccine effectiveness during ongoing malignancy. In this study, using preclinical models, we found that the tumor-suppressed COVID-19 vaccine responses are largely reverted in the setting of PD-1/PD-L1 ICB therapy. We also identified that the PD-1/PD-L1 blockade-directed restoration of COVID-19 vaccine effectiveness is irrelevant to anti-tumor therapeutic outcomes. Mechanistically, the restored COVID-19 vaccine effectiveness is entwined with the PD-1/PD-L1 blockade-driven preponderance of follicular helper T cell and germinal center responses during ongoing malignancy. Thus, our findings indicate that PD-1/PD-L1 blockade will greatly normalize the responses of cancer patients to COVID-19 vaccination, while regardless of its anti-tumor efficacies on these patients.     

PD-1及其配体在慢性乙型肝炎发病机制中的研究进展

PD-1(programmed cell death 1)是近年新发现的一个负性共刺激信号分子,其配体为PD-L1和PD-L2,同属于CD28/B7家族.PD-1/PD-L通路能削弱、限制和/或终止T细胞和APC等细胞的活化及效应功能,在慢性HBV感染的发病机制中发挥了重要作用.     

Vaccination with Leishmania mexicana LPG induces PD-1 in CD8 and PD-L2 in macrophages thereby suppressing the immune response: A model to assess vaccine efficacy

Leishmania lipophosphoglycan (LPG) is a molecule that has been used as a vaccine candidate, with contradictory results. Since unsuccessful protection could be related to suppressed T cell responses, we analyzed the expression of inhibitory receptor PD-1 in CD8⁺ and CD4⁺ lymphocytes and it is ligand PD-L2 in macrophages of BALB/c mice immunized with various doses of Leishmania mexicana LPG and re-stimulated in vitro with different concentrations of LPG. Vaccination with LPG enhanced the expression of PD-1 in CD8⁺ cells. Activation molecules CD137 were reduced in CD8⁺ cells from vaccinated mice. In vitro re-stimulation enhanced PD-L2 expression in macrophages of healthy mice in a dose-dependent fashion. The expression of PD-1, PD-L2 and CD137 is modulated according to the amount of LPG used during immunization and in vitro re-stimulation. We analyzed the expression of these molecules in mice infected with 1 × 10⁴ or 1 × 10⁵L. mexicana promastigotes and re-stimulated in vitro with LPG. Infection with 1 × 10⁵ parasites increased the PD-1 expression in CD8⁺ and diminished PD-L2 in macrophages. When these CD8⁺ cells were re-stimulated in vitro with LPG, simulating a second exposure to parasite antigens, PD-1 expression increased significantly more, in a dose dependent fashion. We conclude that CD8⁺ T lymphocytes and macrophages express inhibition molecules according to the concentrations of Leishmania LPG and to the parasite load. Vaccination with increased amounts of LPG or infections with higher parasite numbers induces enhanced expression of PD-1 and functional inactivation of CD8⁺ cells, which can have critical consequences in leishmaniasis, since these cells are crucial for disease control. These results call for pre-vaccination evaluations of potential immunogens, specifically where CD8 cells are required, since inhibiting molecules can be induced after certain thresholds of antigen concentrations. We propose that the analysis of PD-1 and PD-L2 are useful tools to monitor the optimal dose for vaccination candidates.     

肝包虫病合并HBV感染患者Th17、CD4+细胞表面PD-1/PD-L1的表达水平及意义

目的探讨肝包虫合并乙型肝炎病毒(HBV)感染患者辅助性T细胞17(Th17)、CD4⁺细胞表面程序性死亡分子-1/程序性死亡分子1配体(PD-1/PD-L1)的表达水平及其临床意义。方法选取2014年9月一2019年9月新疆医科大学第一附属医院收治的肝包虫病患者作为研究对象﹐其中100例肝包虫病合并HBV感染患者为合并HBV感染组,肝包虫病无HBV感染患者88例为非HBV感染组﹐采用流式细胞仪检测外周血Th17,CD4⁺细胞表面PD-1,PD-L1表达水平。结果合并HBV感染组患者乙型肝炎家族史,B~C Child分级占比均高于非HBV感染组(P<0.05);肝功能指标[谷丙转氨酶(ALT)、谷草转氨酶(AST),γ-谷氨酰转肽酶(γ-GT)]水平以及Th17 PD-1、Th17 PD-L1,CD,PD-1,CD4⁺PD-L1表达水平均高于非HBV感染组(P<0.05);Child分级A级肝包虫病患者的Th17 PD-1,Th17 PD-L1,CD4⁺PD-1,CD4⁺PD-L1表达水平均低于Child分级B~C级患者(P<0.05)。结论HBV感染会影响肝包虫病患者的肝功能及外周血Th17,CD4⁺细胞表面PD-1,PD-L1表达水平,肝功能严重程度可能与外周血Th17,CD4⁺细胞PD-1,PD-L1表达存在关系。     

新型冠状病毒肺炎实验室诊断技术研究进展

 

2019年12月,湖北省武汉市发现以肺部病变为主的新型冠状病毒感染,2020年2月11日世界卫生组织（WHO）将由新型冠状病毒引发的疾病正式命名为2019冠状病毒病（coronavirus disease 2019,COVID-19）,该病毒称为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。COVID-19短时间内扩散到全国,3月11日WHO宣布COVID-19已构成全球大流行。实验室检测是确诊COVID-19的重要依据,对于该病的治疗和防疫工作至关重要。本文对COVID-19实验室临床诊断技术相关进展进行整理综述。

     

Impaired hepatitis B vaccine responses during chronic hepatitis C infection: involvement of the PD-1 pathway in regulating CD4(+) T cell responses

Vaccination for hepatitis B virus (HBV) in the setting of hepatitis C virus (HCV) infection is recommended, but responses to vaccination are blunted when compared to uninfected populations. The mechanism for this failure of immune response in HCV-infected subjects remains unknown but is thought to be a result of lymphocyte dysfunction during chronic viral infection. We have recently demonstrated that PD-1, a novel negative immunomodulator for T cell receptor (TCR) signaling, is involved in T and B lymphocyte dysregulation during chronic HCV infection. In this report, we further investigated the role of the PD-1 pathway in regulation of CD4⁺ T cell responses to HBV vaccination in HCV-infected individuals. In a prospective HCV infected cohort, a poor response rate to HBV vaccination as assayed by seroconversion was observed in HCV-infected subjects (53%), while a high response rate was observed in healthy or spontaneously HCV-resolved individuals (94%). CD4⁺ T cell responses to ex vivo stimulations of anti-CD3/CD28 antibodies or hepatitis B surface antigen (HBsAg) were found to be lower in HBV vaccine non-responders compared to those responders in HCV-infected individuals who had received a series of HBV immunizations. PD-1 expression on CD4⁺ T cells was detected at relatively higher levels in these HBV vaccine non-responders than those who responded, and this was inversely associated with the cell activation status. Importantly, blocking the PD-1 pathway improved T cell activation and proliferation in response to ex vivo HBsAg or anti-CD3/CD28 stimulation in HBV vaccine non-responders. These results suggest that PD-1 signaling may be involved in impairing CD4⁺ T cell responses to HBV vaccination in subjects with HCV infection, and raise the possibility that blocking this negative signaling pathway might improve success rates of immunization in the setting of chronic viral infection.     

前降钙素在慢性病毒性肝炎合并严重感染时的变化和意义

目的　分析慢性病毒性肝炎合并严重感染时血清前降钙素的变化及其与炎症因子、介质的关系。方法对 31例慢性病毒性肝炎合并自发性细菌性腹膜炎和败血症的患者 ,测定其血清和腹水的前降钙素 (PCT)、肿瘤坏死因子 (TNF)、内毒素 (LPS)和C反应蛋白 (CRP)。结果　合并严重感染时 ,PCT明显增高 ,增高幅度与感染程度呈正比 ,且与未合并感染者的差异有显著性 (P <0 .0 5 ) ;同时还发现PCT的增高与TNF ,LPS和CRP的升高呈正相关。结论　PCT是诊断慢性病毒性肝炎合并严重细菌感染的一个新型、敏感的实验室指标 ,对于鉴别感染与否 ,是否为细菌性感染具有较好的特异性。     

Genetic polymorphisms and surface expression of CTLA-4 and PD-1 on T cells of silica-exposed workers

Exposure to silica dust has been examined as a possible risk factor for autoimmune diseases, including scleroderma, rheumatoid arthritis and systemic lupus erythematosus. Since CTLA-4 [CD152] and PD-1 [CD279] are important for the maintenance of peripheral tolerance by regulating T cell responsiveness, we evaluated the expression of these molecules on the surface of CD4 and CD8 T cells, as well as single nucleotide polymorphisms (SNP) in CTLA-4 and PDCD1 genes, of 70 silica-exposed workers and 30 non-exposed, age-, ethnically- and sex-matched controls. Expression of CTLA-4 was significantly (P<0.05) reduced in CD4 T cells of exposed individuals [median=0.1% and interquartile range, IQR 0.0-0.1% (exposed), median=0.20%, IQR 0.0-0.4% (control)]. Also the expression of PD-1 was significantly (P<0.0001) reduced in both CD4 [median=0.9%, IQR 0.4-2.3% (exposed), median=5.7%, IQR 1.4-13.3% (control)] and CD8 T cells [median=0.9%, IQR 0.3-1.9% (exposed), median=5.0%, IQR 3.4-8.9% (control)]. The study of polymorphisms demonstrated a lower frequency of the A allele in the analysis of the PD1.3 SNP in the exposed group, which might be associated with the lower expression of PD-1 on the surface of CD4 T cells. Our findings provide evidence for the association of silica exposure and the maintenance of self-tolerance, i.e., the susceptibility to autoimmune disorders.