Treg细胞与Th17细胞的研究现状及临床意义

CD4+辅助性T细胞是一类重要的免疫调节细胞.传统观点认为CD4+辅助性T细胞,特别是Th1和Th2细胞能够反映机体的免疫功能状态.CD4+CD25+调节性T细胞(regulatory tcells, Treg)和辅助T细胞17是新发现的Th细胞亚群,它们在维持机体免疫平衡方面发挥重要作用[1-3],是对Th1和Th2免疫平衡理论的重要补充,成为免疫学和肿瘤学等领域的研究热点[4].炎症、感染、肿瘤、自身免疫性疾病等多种疾病状态中Th17、Treg细胞免疫失衡也有不少报道[5-7].本文就Treg细胞及Th17细胞的研究现状及临床意义做一综述.     

Th17细胞在自身免疫性疾病中的研究进展

经典的Th1和Th2模式为人们理解CD4+T细胞的生物学特性以及固有免疫和适应性免疫提供了基本框架.近来,新发现的Th17细胞以优先产生IL-17、IL-17F和IL-22等细胞因子为特征,它不仅参与宿主防御免疫而且在自身免疫方面起重要作用.这种新的效应T细胞的发现改变了传统的对宿主免疫防御、免疫调节和免疫致病的理解.此文就Th17细胞在自身免疫性疾病中的研究进展作一综述.     

Th17细胞在病原微生物感染中的作用研究进展

病原微生物以人体为栖息地、传播中转站和能量来源。人类从诞生之日起就不断和病原微生物作斗争,免疫系统是人体强大的＂化学武器＂。如何提升机体免疫功能以有效控制病原微生物感染已成为医学研究难题。20世纪80年代末至90年代中后期陆续发现了包括Th1、Th2、Treg等CD4＋T细胞亚群,在理论及实践中解释了许多免疫反应原理,但不能完全解释某些免疫相关疾病过程,CD4＋Th17细胞的发现丰富了我们对机体免疫机制的认识。Th17由初始T淋巴细胞分化而来,通过分泌IL-17,在防御胞外病原菌感染、自身免疫性疾病和过敏性疾病、心血管疾病、肿瘤、移植免疫等方面发挥重要作用。本文就Th17细胞在病原微生物感染中的作用作一综述。     

反复呼吸道感染患儿外周血CD4~+CD25~+CD127~-调节性T细胞的表达

<正>反复呼吸道感染(RRTI)是小儿时期的常见病,其发生的原因与诸多因素有关。CD4+CD25+T调节细胞(regulatory T cell,Tr/Treg)是一个具有独特免疫调节功能的T细胞亚群。此亚群细胞可抑制性调节CD4+或CD8+T细胞活化与增殖,在免疫应答中发挥调节作用[1]。目前对CD4+CD25+CD127-调节性T细胞(Treg细胞)与RRTI的相关研究报道较少。本研     

Th17细胞在变应性鼻炎中的作用

目的 探讨一种新型的不同于Th1和Th2的CD4+效应T细胞-辅助性17细胞(T help 17,Th17)在变应性鼻炎中的作用.方法 应用冰冻切片加免疫组化对30例变应性鼻炎病例组及30例对照组进行检测,观察Th17阳性数;并应用ELISA法测定各组的IL-17水平.结果 在变应性鼻炎组中Th17细胞有明显的表达,白介素17(interleukin 17,IL-17)水平也明显增高.结论 ,Th17细胞及其细胞因子IL-17在变应性鼻炎的发病过程及临床治疗中有重要的作用.     

Th1/Th2免疫应答与疾病

198 6年 Mosmann等根据鼠的辅助性 T细胞 (Th)分泌的细胞因子及生物学功能不同 ,首次提出 Th细胞分为 Th1细胞和 Th2细胞。 1991年 Maggi等证实 ,人的 Th细胞与鼠类似 ,也可分为 Th1和 Th2两类。Th1和 Th2的区分迅速在免疫学各个领域得到广泛应用 ,Th1/ Th2免疫应答与临床各类疾病之间关系的认识引起关注。1　人类 Th1和 Th2细胞的生物学特性1.1　产生的细胞因子 :根据产生细胞因子的不同 ,Th可分为Th0、 Th1和 Th2 ,成熟未致敏 (native)细胞为 Th0 ,在抗原刺激及细胞因子参与下 ,分化为 Th1及 Th2细胞。Th1细胞产生 IL- 2、IFN…     

Treg细胞与Thl7细胞的研究现状及临床意义

CD4^＋辅助性T细胞是一类重要的免疫调节细胞。传统观点认为CD4^＋辅助性T细胞,特别是Thl和Th2细胞能够反映机体的免疫功能状态。CD4^＋CD25^＋调节性T细胞（regulatorytcells,Treg）和辅助T细胞17是新发现的Th细胞亚群,它们在维持机体免疫平衡方面发挥重要作用,是对Thl和Th2免疫平衡理论的重要补充,成为免疫学和肿瘤学等领域的研究热点。     

强直性脊柱炎外周血Th17细胞的检测及意义

目的 探讨Th17细胞在强直性脊柱炎(AS)患者外周血中的水平及意义.方法 取40例AS患者(分AS病情稳定组、活动组各20例)和健康人外周血单个核细胞(PBMC),免疫磁珠阴选CD4~+ T细胞,用或不用非特异性刺激剂(A-CD3、A-CD28),然后加PMA/Ion,经固定/透膜处理进行细胞内染色,流式细胞术(FCM)检测CD4~+T细胞内白细胞介素17(IL-17~+)/γ于扰素(IFN-γ~+)、IL-17~+/IL-6~+水平.结果 免疫磁珠阴选CD4~+T细胞纯度达90% 以上.AS病情活动组IL-17表达水平较病情稳定组和健康对照组显著增高(P<0.01).用A-CD3、A-CD28和IL-23刺激后,CD4~+ T细胞IL-17胞内表达水平较无刺激有一定的增加.AS患者CD4~+T细胞IFN-γ胞内表达水平呈现卜IL-17表达相似的特点.AS患者IL-17胞内表达水平与IFN-γ和IL-6无显著相关.结论 AS患者外周血CD4~+ T细胞胞内IL-17和IFN-γ高表达,提示分泌IL-17的Th17细胞和分泌IFN-γ的Th1细胞共同参与了AS发病过程.     

Th17细胞与银屑病关系的研究进展

Th17细胞是近年来发现的一种CD4^＋T细胞新亚型,并与银屑病及其他自身免疫性疾病的发病密切相关。Th17细胞主要通过IL-23／Th17细胞轴引起并加剧银屑病患者皮损中慢性免疫性炎症,由Th17细胞产生的IL-22在银屑病的发病机制中发挥关键作用。Th17细胞是如何由外周组织迁移到真皮层？Th17细胞与银屑病的发生和加重有何关系？了解Th17细胞分化所需要的特殊转录因子、表面表达分子、分泌的细胞因子对进一步认识银屑病免疫病理过程及发现潜在治疗靶点有很大帮助。     

DC-SIGN的研究进展

树突状细胞(DC细胞)是体内最重要的专职抗原提呈细胞,目前发现DC既能启动初始免疫应答,也能负向调控免疫反应[1].DC细胞的这种免疫调节与DC表面的诸多受体分子,尤其是作为抗原受体的C型凝集素受体(CLR)及Toll受体(LR)有关.它们能识别抗原进而通过不同的方式进行抗原呈递.其中,CLR是通过识别病原体的碳水化合物结构,并将其内化完成抗原的呈递和表达,继而诱导不同亚群T细胞的活化,发挥特异性免疫功能,诱导机体产生特异性免疫应答.在上述一系列生化反应中,作为DC之CLR主要成员的多功能免疫分子DC-SIGN (DC-sepecific ICAM- grabbing non-integrin)起到了重要作用.DC -SIGN,又称CD209,最初由美国科学家于2000年在研究人类免疫缺陷病毒(HIV)感染机制中发现,因其能与HIV-1包膜蛋白(gp120)结合,介导DC致CD4+T细胞感染HIV造成免疫缺陷,故也称其为HIV-1gp120结合C型凝集素[2,3].由于发现该C型凝集素介导DC与初始T细胞表面ICAM-3结合无需整合素,但必须有Ca2+参与,故而被命名为DC-SIGN.     

17 -Propadienyl, 17 -propynyl, and 17 -trifluoropropynyl analogs of 6,6-difluoronorethindrone

The synthesis of analogs of 6,6-difluoronorethindrone (la) is reported. The new compounds, each of which are potent oral progestational agents, are ( )-6,6-difluoronorgestrel (lb), 17 beta-hydroxy-6,6-difluoro-17alpha-propadienyl-4-estren-3-one (lc), 17beta-hydroxy-6,6-difluoro-17alpha-(1-propynyl)-4-estren-3-one (ld), and 17 beta-hydroxy-6,6-difluoro-17alpha-(3,3,3-trifluoropropynyl)-4-estren-3-o ne (le). The 6,6-gem-difluoro group is an important means for enhancing the progestational activity of parent compounds. Compounds lc,ld, and le were prepared from a common precursor, 6,6-difluoro-4-estrene-3,17-dione 3-ethylene ketal. The findings indicate that 6,6-difluoro steroids are stable towards a variety of reagents. The experimental procedures are summarized.     

Clinical development of 17-allylamino, 17-demethoxygeldanamycin

17-allylamino, 17-demethoxygeldanamycin (17AAG; NSC 330507) is the first modulator of heat shock protein 90 (Hsp90) to enter clinical trials. Hsp90 serves a chaperone role to properly fold and deliver client proteins to appropriate intracellular locations. Interest in Hsp90 modulators for the experimental therapeutics of cancer has arisen based on pre-clinical evaluations suggesting that Hsp90 client proteins regulate signaling pathways critical to the molecular economy of many types of tumors, including oncogene signaling, cyclin-dependent kinase activation, steroid hormone receptors, and mediators of invasion and metastasis. Thus, Hsp90-directed agents could affect molecules upon which tumors depend for their proliferation and survival. Initial clinical studies have therefore sought to incorporate assessment of these endpoints into initial clinical evaluations. Three schedules of administration have been supported for initial evaluation in Phase I studies sponsored by the National Cancer Institute (NCI) or supported by NCI and sponsored by Cancer Research UK. In the daily times five schedule, a recommended Phase II dose (RPTD) of 40 mg/m(2) has been reached, while once weekly or three of four weekly schedules are defining RPTDs of 295 and 308 mg/m(2). Toxicity is tolerable and appears dominated by hepatic, gastrointestinal, and constitutional symptoms. Concentrations of drug at peak of ~1700-3000 nM are concordant with concentrations predictive of useful outcomes in pre-clinical model systems. Evidence of modulation of Hsp90 partner molecules has been obtained in both surrogate and some tumor compartments. These very early results encourage additional clinical evaluations of 17AAG and related molecules.     

Synthesis and evaluation of 17-aliphatic heterocycle-substituted steroidal inhibitors of 17alpha-hydroxylase/C17-20-lyase (P450 17)

In the search for potent inhibitors of P450 17, the key enzyme in androgen biosynthesis, a series of steroidal inhibitors were synthesized and tested toward rat and human P450 17. Small aliphatic heterocycles (aziridine, oxirane, thiirane, diaziridine, diazirine, azetidine) were introduced into the 17beta-position of anstrost-5-en-3beta-ol. After identifying that aziridine is the most suitable functional group to coordinate with the heme iron, modifications of the steroidal skeleton were performed for further optimization. A wide range of inhibitory potencies toward P450 17 were found for the 21 test compounds. The most potent inhibitors toward the human and rat enzyme were aziridine compounds 3 (IC(50) rat: 0.21 microM, K(i) = 3 nM; IC(50) human: 0.54 microM, K(i) = 8 nM), 5 (IC(50) rat: 0.43 microM, K(i) = 7 nM; IC(50) human: 0.29 microM, K(i) = 4 nM), and 8 (21R:21S = 1:1; IC(50) rat: 0.53 microM, K(i) = 9 nM; IC(50) human: 0.40 microM, K(i) = 6 nM) which were more potent than the reference ketoconazole (IC(50) rat: 67 microM; IC(50) human: 0.74 microM). The inhibitory potency depends markedly on the stereochemistry at C20 of the inhibitors. This effect is more pronounced for the rat enzyme. Tested for selectivity, the highly potent inhibitors show poor inhibitory activity toward P450 arom, P450 scc, P450 TxA(2), and 5alpha-reductase. Tested for in vivo activity, 3 and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats by 81% and 84% after 2 h.     

Th17细胞与白介素17在鼻息肉中的研究进展

白介素17是Th17细胞产生的炎性细胞因子,研究发现IL-17在鼻息肉组织中明显增多,且可能参与了鼻息肉形成过程中的黏膜重建并促进了血管生长因子的高表达,但其机制尚未明确。本文参阅近几年相关文献,就Th17细胞的分化及其产生的IL-17在鼻息肉中的作用做一综述。     

17-Allylamino-17-demethoxygeldanamycin overcomes TRAIL resistance in colon cancer cell lines

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising candidate for treatment of cancer, but displays variable cytotoxicity in cell lines. The mechanisms of sensitivity and resistance have not been fully elucidated; both AKT and NF-kappaB pathways may modulate cytotoxic responses. We have shown that the Hsp90 inhibitor 17-AAG enhances the cytotoxicity of oxaliplatin in colon cancer cell lines through inhibition of NF-kappaB. We analyzed the effects of TRAIL and 17-AAG in combination in a series of nine colon cancer cell lines and characterized activation of the pathways to apoptosis. IC(50) values for a 72 h exposure to TRAIL ranged from 30 to 4000 ng/ml. Cytotoxicity assays demonstrated additivity or synergism of the TRAIL/17-AAG combination in all cell lines, with combination indices at IC(50) ranging from 0.53 to 1. The sensitizing effect of 17-AAG was greater in the TRAIL-resistant cell lines. In TRAIL-resistant cell lines, the combination of 17-AAG and TRAIL resulted in activation of both extrinsic and intrinsic apoptotic pathways, though with quantitative differences between HT29 and RKO cells: differential effects of 17-AAG on AKT and NF-kappaB characterized these cell lines. In both cell lines, the combination also led to down-regulation of X-linked inhibitor of apoptosis protein (XIAP) and enhanced activation of caspase-3. We conclude that either AKT or NF-kappaB may promote resistance to TRAIL in colon cancer cells, and that the ability of 17-AAG to target multiple putative determinants of TRAIL sensitivity warrants their further investigation in combination.     

17-Desoxy estrogen analogues

A series of 17-substituted, 17-desoxyestratrienes have been synthesized and tested as potential postcoital antifertility agents. Estrogen-relative binding affinities were determined, in vivo assays for estrogenic and postcoital antifertility activity were conducted in rats, and selected candidate compounds were further tested for estrogenic activity in monkeys. In the rat, the 17-desoxyestratriene derivatives 8a, 8b, and 30 have shown low estrogenic activity while retaining potent antifertility activity. Structural modifications at the outset included a variety of 17-substituents and an omission of the 17-oxygen functionality, which was previously thought to be necessary for potent activity. The 17 beta-ethyl side chain exhibited the greatest antifertility activity with the largest separation ratio to estrogenicity. Nuclear modification of 17-desoxyethylestrane derivatives at positions 7 and 11 further increased the desired separation of activity, with the 11-hydroxy moiety enhancing separation more than other features.