T细胞在动脉粥样硬化性心血管疾病中的研究进展

<正>冠状动脉粥样硬化(AS)性心脏病是心血管系统最常见的疾病之一，我国发病率呈逐年上升趋势^[1]。在AS的发生和发展过程中，先天性免疫细胞[中性粒细胞、单核细胞、巨噬细胞、树突细胞(DC)]与获得性免疫细胞(T和B淋巴细胞)之间存在紧密的相互作用。成熟斑块的特征是脂质池富含先天免疫细胞和获得性免疫细胞(T、B淋巴细胞)和氧化的低密度脂蛋白(LDL),其周围由平滑肌细胞(SMC)和胶原蛋白基质形成纤维帽^[2]。     

CD40/CD40L参与动脉粥样硬化的机制

CD40/CD40L在T淋巴细胞和B淋巴细胞的活化及其介导的体液免疫过程中起重要作用,CD40/CD40L相互作用是淋巴细胞之间传递炎症和免疫信号的重要途径。近年来发现,CD40/CD40L广泛存在于动脉粥样硬化(AS)斑块的各种细胞中,其相互作用显著影响AS相关细胞的功能,并且与斑块的发生发展密切相关,本文主要讨论CD40/CD40L在AS病变及相关细胞中的表达、参与AS过程的机制、信号转导途径以及基因表达的调节。1CD40/CD40L在AS病变及相关细胞中的表达正常动脉未发现CD40L,仅在内皮细胞有少量CD40表达。在人类AS发生过程中,CD40/CD40L在T…     

树突状细胞与肺部疾病关系研究现状

树突状细胞(DC)是功能最强的抗原呈递细胞(APC).与其他APC如巨噬细胞、B细胞相比,DC具有独特的刺激处女(naive)型T细胞的能力.DC在启动免疫方面及决定免疫走向方面起着关键作用.肺部DC主要存在于气道和靠近肺泡的间质中.许多肺部疾病与DC有关.本文综述DC在肺部的分布,DC的成熟和功能,DC与T、B淋巴细胞,以及DC与哮喘、肺部肿瘤、支气管扩张等肺部疾病的关系,其中重点综述DC与哮喘的关系.     

大鼠动脉粥样硬化斑块中T淋巴细胞亚群及Kv1.3通道蛋白的表达

目的探究Kv1.3通道蛋白与动脉粥样硬化(AS)模型中活化的T淋巴细胞间的关系。方法 Wistar雄性大鼠24只,随机分为对照组(n=10)和AS组(n=14),采用高脂饲料喂养方法建立AS模型。分别于实验开始前,实验第8周,实验第12周观察各组大鼠体重变化。于第12周处死大鼠前取血,检测血清中总胆固醇(TC)、低密度脂蛋白(LDL-L)、高密度脂蛋白(HDL-L)和甘油三酯(TG)的水平。通过病理HE染色及免疫组织化学方法观察AS斑块内T淋巴细胞亚群分布和Kv1.3通道蛋白表达的改变。结果 AS组体重、TC、LDL-C较对照组明显升高(P均<0.05);HDL-C和TG两组无差异。AS组主动脉管壁可见明显斑块形成,对照组血管壁各层的组织结构正常。AS组动脉斑块部位内膜下及中膜层可见CD4+与CD8+T淋巴细胞聚集,以CD4+T淋巴细胞聚集为主,在病变部位Kv1.3通道蛋白表达增加。对照组血管内膜、中膜中未见T淋巴细胞聚集及KV1.3通道蛋白的表达。结论 Kv1.3通道可能在调节AS斑块部T淋巴细胞亚群的激活中起着重要作用。     

辅助性T细胞17及调节性T细胞与动脉粥样硬化关系研究进展

<正>动脉粥样硬化(AS)是一种多因素引起的慢性炎性血管性疾病。传统观点简单地认为,AS是由血管壁脂质沉积引起。随着研究的深入,越来越多的证据表明,免疫介导的炎性反应在AS发生发展中发挥重要作用,其中CD4T淋巴细胞尤为重要[1]。新近研究表明,辅助性T细胞(Treg)17(Th17)及调节性Treg是不同于Th1、Th2的CD4T淋巴细胞新亚群,两者在功能上相互拮抗[2]。Treg可抑制AS发生     

树突状细胞诱导抗胃癌移植瘤免疫

目的　研究树突状细胞 (DC)体外诱导的抗肿瘤免疫能否抑制裸鼠移植瘤生长并预防其发生。方法　联合应用粒 /巨噬细胞集落刺激因子 (GM -CSF)及白介素 4(IL 4)直接从胃癌患者外周血中培养出DC ;以SGC -790 1细胞的肿瘤抗原粗提物刺激DC使其激活同源的T淋巴细胞产生细胞毒性T淋巴细胞 (CTL) ;建立裸鼠SGC -790 1细胞移植瘤模型 ;DC诱导的CTL治疗裸鼠SGC -790 1细胞移植瘤 ,观察移植瘤生长 ;DC诱导的CTL预防性治疗裸鼠 ,观察随后接种的SGC -790 1细胞移植瘤发生情况。结果　DC诱导的CTL不仅能抑制裸鼠移植瘤生长并能预防其发生。结论　经肿瘤抗原激活的DC作为一新概念上的抗肿瘤疫苗有可能在治疗肿瘤及预防其术后复发和转移中发挥重要作用。     

核因子-κB与动脉粥样硬化

动脉粥样硬化 (AS)及其并发症是人群致病和死亡的重要原因。AS被认为是一种动脉慢性炎症的病理过程。核因子 κB(NF κB)在其中起主要作用。1　动脉粥样硬化与炎症AS是一个以炎症反应和纤维细胞增殖为特征的慢性炎症过程。在AS的血管组织中发现大量巨噬细胞和T淋巴细胞聚集 ,这些细胞释放白细胞黏附分子、细胞因子、生长因子 ,导致血管平滑肌细胞增殖和泡沫细胞形成 ,导致AS斑块的形成。炎症在斑块破裂中起重要作用。大约 50 %的急性冠脉综合征 (ACS)是因斑块不稳定破裂 ,继发血栓形成所致。研究发现 ,ACS病人血中巨噬细胞和T淋巴…     

树突状细胞激活的肿瘤浸润性淋巴细胞抗胃癌活性的研究

目的　树突状细胞 (DC)是目前已知的功能最强的抗原提呈细胞 (APC) ,可以向包括肿瘤浸润性淋巴细胞 (TIL)在内的T淋巴细胞提呈抗原 ,并诱发细胞毒T淋巴细胞 (CTL)反应。该文探讨树突状细胞激活的肿瘤浸润性淋巴细胞体外对胃癌细胞 (SGC 790 1 )的杀伤活性。方法　从胃癌患者外周血获取DC ,应用粒 /巨噬细胞集落刺激因子 (GM CSF)、白介素 4(IL 4)和肿瘤抗原激活DC ,然后用DC激活TIL ,观察TIL在体外对自体胃癌细胞和人胃癌细胞株细胞的杀伤活性。结果　DC激活的TIL具有很高的对自体胃癌细胞杀伤活性 ,杀伤率为 (89.39± 3 .0 5) % ,明显高于未经DC激活的TIL、CD激活的T淋巴细胞和未经DC激活的T淋巴细胞对自体胃癌细胞的杀伤率 [杀伤率分别为 (54 .37±1 .50 ) % ,(53 .92± 1 .46) %和 (3 .55± 0 .2 5) % ]。而它们对SGC 790 1细胞的杀伤活性则相对较低。结论　胃癌患者外周血DC能诱导TIL产生高效而特异的抗胃癌免疫     

MAGE-3抗原肽致敏树突状细胞的体内抗膀胱癌作用及机制

目的 探讨黑色素瘤-3基因(MAGE-3)抗原肽致敏的树突状细胞(DC)体内对膀胱癌肿瘤的抑制作用及机制.方法 采用Ficoll法从HLA-A2型个体外周血中分离单个核细胞,用GM-CSF和IL-4诱导扩增DC,再经MAGE-3抗原肽致敏,致敏DC细胞和同型T淋巴细胞共培养诱导细胞毒性T淋巴细胞(CTL),经过尾静脉注入膀胱癌荷瘤小鼠,观察其对肿瘤体积及重量的影响.结果 MAGE-3抗原肽致敏的DC诱导产生的CTL可明显缩小瘤体、降低瘤重.结论 MAGE-3九肽致敏DC诱导CTL体内具有抑制膀胱癌细胞增长的作用;其机制可能为激活T淋巴细胞.     

动脉粥样硬化大鼠主动脉内膜增生与树突状细胞分布的关系

目的:探讨动脉粥样硬化(AS)大鼠树突状细胞(DCs)在外周血、动脉壁以及脾脏分布情况及与主动脉内膜增生的关系。方法:经高脂饮食喂养12周形成AS大鼠模型,分别取外周血、动脉壁以及脾脏组织,并制备组织单细胞悬液。应用流式细胞仪检测DCs及T淋巴细胞比例。结果:AS大鼠主动脉壁内膜较正常对照大鼠内膜增生明显(P<0.05),其外周血DCs分布明显减少且主动脉壁内DCs比例明显升高(P<0.001)。T淋巴细胞比例检测发现,AS大鼠较正常大鼠,外周血及主动脉壁内T淋巴细胞比例均升高(P<0.001)。结论:AS大鼠主动脉内膜增生与DCs及T淋巴细胞比例变化有关,DCs在AS大鼠主动脉内膜增生、管壁粥样硬化形成中可能起重要作用。     

Dendritic cells in atherosclerosis: current status of the problem and clinical relevance.

Dendritic cells (DCs) are the most potent antigen-presenting cells. DCs were identified in arteries in 1995 and, since then, further knowledge has been gained indicating the importance of DCs in atherosclerosis. Vascular DCs have been shown to become activated from a very early stage of atherosclerosis. Some DCs cluster with T cells directly within atherosclerotic lesions, while others migrate to lymphoid organs to activate T cells. Dyslipidaemia systemically alters DC function and recent findings suggest that DCs play a role in plaque destabilization. This review summarizes the current status of the problem.     

Emerging role of chemokine receptor 7 in atherosclerosis

The CC chemokine receptor 7 (CCR7) and its ligands CCL19 and CCL21 essentially contribute to both immunity and tolerance by directing T cells and antigen-presenting dendritic cells (DCs) to and within lymph organs. In the pathogenesis of atherosclerosis, the accumulation of cholesterol in the subendothelial space of the vessel wall represents the initial step of plaque development in which DCs acquire and process low-density lipoprotein cholesterol as antigen in the vessel wall and then migrate to draining lymph nodes and present this antigen to naive T cells. Deletion of CCR7 receptor in murine atherosclerosis not only results in a reduced atherosclerotic plaque content but also leads to a disturbed entry and exit of T cells within the inflamed vessel wall. These observations are consistent with the notion that CCR7-dependent T cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue is pivotal for atherosclerotic plaque development and may represent an interesting target for innovative immune-modulatory therapy.     

Role of dendritic cells in cardiovascular diseases

Dendritic cells (DCs) are potent antigen-presenting cells that bridge innate and adaptive immune responses. Recent work has elucidated the DC life cycle, including several important stages such as maturation, migration and homeostasis, as well as DC classification and subsets/locations, which provided etiological insights on the role of DCs in disease processes. DCs have a close relationship to endothelial cells and they interact with each other to maintain immunity. DCs are deposited in the atherosclerotic plaque and contribute to the pathogenesis of atherosclerosis. In addition, the necrotic cardiac cells induced by ischemia activate DCs by Toll-like receptors, which initiate innate and adaptive immune responses to renal, hepatic and cardiac ischemia reperfusion injury (IRI). Furthermore, DCs are involved in the acute/chronic rejection of solid organ transplantation and mediate transplant tolerance as well. Advancing our knowledge of the biology of DCs will aid development of new approaches to treat many cardiovascular diseases, including atherosclerosis, cardiac IRI and transplantation.     

The role of T-lymphocyte subpopulations in acute myocardial infarction

T lymphocytes have the potential to affect atherosclerosis at different stages of the process. They play an active role in acute myocardial infarction (AMI) and myocardial damage, and may affect the clinical outcome of patients with coronary artery disease. CD40 ligand expression on T lymphocytes promotes the expression of matrix-degrading enzymes in vascular smooth muscle cells and may thus establish a new pathway of immune-mediated destabilization of the human atheroma. The major class of T lymphocytes present in atherosclerotic lesions is CD4+. CD4+ cells differentiate into Th1 and Th2 lineage in response to the local milieu of cytokines. Much of the emphasis in atherosclerosis research is focused on the role of Th1 type responses.     

Decreased production of inflammatory cytokines by circulating monocytes and dendritic cells in type 2 diabetic men with atherosclerotic complications

Antigen-presenting cells (APCs) are involved in the development of atherosclerosis, whose complications represent the main cause of death in diabetic patients. Nevertheless, their role in atherogenesis is poorly understood. We compared the number of circulating monocyte and dendritic cell (DC) subsets as well as their capacity to produce inflammatory cytokines IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) in type 2 diabetic men with (n=11) and without (n=44) chronic atherosclerotic complications. Identification and enumeration of peripheral blood (PB) lymphoid subsets, monocytes, myeloid (CD33strong+), CD16+, and plasmacytoid (CD33-/dim+) DCs as well as of their spontaneous and stimulated production of IL-1beta, IL-6, and TNF-alpha were performed at the single-cell level by flow cytometry. Our results show that type 2 diabetic men with atherosclerotic complications display a significantly reduced spontaneous secretion of IL-6 by monocytes and CD16+ DCs and of TNF-alpha by CD16+ DCs as compared to patients without atherosclerotic complications. Spontaneous secretion of IL-1beta by monocytes and CD16 DCs and of IL-6 by CD33+ and plasmacytoid DCs was detected in patients without atherosclerotic complications but not in the other patients with complications. Taken together, these results indicate that type 2 diabetic men with atherosclerotic complications display both quantitatively and functionally impaired immunological responses by circulating APCs. The decreased patterns of inflammatory cytokine production by these cells may influence the inflammatory response mediated by APCs as well as the antigen-specific responses mediated by other cells such as T cells.     

T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions

Atherosclerotic lesions are infiltrated by macrophages and T lymphocytes, potentially reactive to pathogens. We studied in vivo activated T lymphocytes that infiltrate atherosclerotic plaques of Helicobacter pylori-infected patients with or without anti-Chlamydia pneumoniae antibodies. In all atherosclerotic lesions, T helper type 1 (Th1) cells were predominant. C. pneumoniae-specific T cells were detected only in the plaques of anti-C. pneumoniae seropositive patients, whereas H. pylori-specific T cells were found in the gastric mucosa but not in the plaques of the same patients. Plaque-derived Th1 cells expressed cytotoxicity, proapoptotic activity, and help for monocyte tissue factor production. Although multifactorial, atherosclerosis can be regarded as a Th1-driven immunopathological condition.     

T lymphocytes that infiltrate tumors and atherosclerotic plaques produce heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor: a potential pathologic role.

Despite significant infiltration into tumors and atherosclerotic plaques, the role of T lymphocytes in these pathological conditions is still unclear. We have demonstrated that tumor-infiltrating lymphocytes (TILs) and plaque-infiltrating lymphocytes (PILs) produce heparin-binding epidermal growth factor-like growth factor (HB-EGF) and basic fibroblast growth factor (bFGF) in vitro under nonspecific conditions and in vivo in tumors by immunohistochemical staining. HB-EGF and bFGF derived from TILs and PILs directly stimulated tumor cells and vascular smooth muscle cells (SMCs) in vitro, respectively, while bFGF displayed angiogenic properties. Therefore, T cells may play a critical role in the SMC hyperplasia of atherosclerosis and support tumor progression by direct stimulation and angiogenesis.     

Detection of Chlamydophila pneumoniae in dendritic cells in atherosclerotic lesions

Dendritic cells (DCs) populate atherosclerotic lesions and might be involved in the regulation of immune reactions in atherosclerosis. The present work was undertaken to examine a possible association of DCs with Chlamydophila pneumoniae in human atherosclerotic plaques obtained by endarterectomy. C. pneumoniae was identified in 17 of 60 (28%) atherosclerotic plaques by a combination of immunohistochemistry and polymerase chain reaction (PCR). Double immunohistochemistry identified the presence of C. pneumoniae within S100(+) DCs that were localised predominantly in the deep layer of the intima under the necrotic core. Quantitative analysis showed that there were no differences in the numbers of DCs between C. pneumoniae(+) and C. pneumoniae(-) groups of atherosclerotic specimens. There were also no differences in the expression of Lag-antigen and HLA-DR by DCs between the groups of specimens. Markers of DC activation CD80 and CD86 were absent from both groups of specimens. Flow cytometry analysis of the effects of C. pneumoniae infection on immature monocyte-derived DCs in vitro showed no changes in the expression of CD1a, MHC class II, CD80 and CD86. The results of this study demonstrate that C. pneumoniae might infect DCs within the atherosclerotic intima but whether the presence of C. pneumoniae in DCs affects the intensity of immune reactions in atherosclerosis needs further clarification.     

Distribution of inflammatory cells in adventitia changed with advancing atherosclerosis of human coronary artery

AIM: Since atherosclerosis was recognized as an inflammatory disease in 1990, the infiltration of macrophages and T lymphocytes has been reported to be predominant in human atherosclerotic lesions. Although adventitis accompanying atherosclerosis was also described in many reports, it is still unclear whether T lymphocytes or B lymphocytes are predominant in the adventitis. In this study, the authors immunohistochemically investigated the correlation between the transition of infiltrating inflammatory cells in the adventitia with atherosclerosis and the type of coronary atherosclerosis. METHODS: Sixty-four coronary atherosclerotic lesions from a surgical specimen and 47 autopsy cases were used for immunohistochemical study of CD45RO, CD20, CD68 and others. Atherosclerosis was classified into type I, II, III, IV according to the 1995 AHA classification. RESULTS: T lymphocyte infiltration in the adventitia was predominantly recognized in about 80% (38/48) of cases, but B lymphocyte infiltration was occasionally recognized in about 20% (10/48). Among 10 cases with B lymphocyte infiltration, small lymph follicles formed in 3 cases. This inflammatory response in adventitia subsided in type III and augmented again in type IV.CONCLUSION: This result suggested that other inflammatory stimuli were induced in the adventitia in type IV coronary atherosclerosis.     

Interleukin-10 and coronary disease

Understanding of the pathophysiology of atherosclerosis has changed markedly over the past few decades. It is now widely accepted that inflammation plays a fundamental role in the genesis and development of atherosclerosis. Inflammatory mechanisms also appear to determine clinical presentation and disease outcome. Atherosclerotic lesions have high concentrations of inflammatory cells (T lymphocytes and activated macrophages) as well as an abundance of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-8, interferon-gamma, tumor necrosis factor-alpha, etc.] that modulate local inflammatory responses. These may also alter plaque stability and facilitate the development of acute cardiovascular events. The role of anti-inflammatory cytokines in this context remains to be studied. IL-10 is an anti-inflammatory cytokine synthesised by T-lymphocytes and macrophages and has other anti-inflammatory effects. IL-10 expression within human atherosclerotic plaques has been demonstrated and animal experiments have shown that low levels of IL-10 lead to the development of extensive and unstable atherosclerotic lesions. Currently available evidence suggests a potential protective role for IL-10 in atherosclerosis. This new perspective on coronary disease as a chronic inflammatory process may open new avenues for the management of ischemic heart disease.