异位性皮炎患者Th17细胞的表达及其意义

既往研究报告Th1/Th2细胞失衡在异位性皮炎发病中起着重要作用,Th1型细胞因子IL-4、IL-5在异位性皮炎中存在过度表达。Th17细胞是独立于Th1/Th2型细胞的一种新型T细胞,能分泌炎症介质白细胞介素17（IL-17）诱导免疫炎症反应[1]。本文旨在探讨Th17、IL-17在异位性皮炎中的表达及其意义。     

急性白血病患儿化疗前后部分细胞因子变化水平及临床意义

近年来发现细胞因子与肿瘤的发生、发展有重要关系,如CD4＋Th细胞通过分泌干扰素-γ等细胞因子以及辅助诱导和激活CD8＋CTL,发挥抗肿瘤作用;但是肿瘤细胞也可通过分泌IL-10等抑制性细胞因子抑制机体抗原提呈细胞、T细胞和固有免疫细胞（包括NK细胞）的功能,导致宿主处于免疫功能低下状态或免疫抑制状态,从而在免疫应答诱导和效应的多个环节上抑制机体抗肿瘤免疫应答。     

白细胞介素17与类风湿关节炎关系的研究进展

白细胞介素17（IL-17）是由CD4^＋记忆T淋巴细胞、CD8^＋细胞、嗜酸性粒细胞等多种细胞分泌的细胞因子，IL-17通过调节许多细胞因子、趋化因子、生长因子、黏附分子及多种酶的功能效应，参与机体免疫调节和炎症反应。自1993年IL-17被发现以来，随着相关研究的日渐深入，已证明许多疾病的发生发展与IL-17相关。     

CD4~+T细胞新亚群——Th9细胞研究新进展

传统意义上的CD4+T细胞在接受外来抗原刺激后经过两类经典途径分化为Th1和Th2细胞,参与体液和细胞免疫应答。除Th1和Th2细胞外,调节性T细胞(Treg)和Th17细胞属于CD4+T细胞,并参与相应的免疫应答反应的结论也     

Th17/Treg失衡与肿瘤免疫

免疫微环境的平衡与肿瘤的发生、发展密切相关,而CD4+T细胞在肿瘤免疫应答中发挥重要的辅助作用.目前研究认为,初始CD4+T细胞在不同条件下可分化成不同亚型的T淋巴细胞,包括Th1、Th2、Th17和调节性T细胞( regulatory T cell,Treg),分别受不同的转录因子调控,在体内发挥不同的生物学功能.Th17细胞与Treg细胞是目前免疫学研究的热点,其不仅参与免疫应答、免疫耐受的调节,在自身免疫性疾病、炎症、移植排斥反应和肿瘤免疫中亦具有重要作用.Th17细胞在分化及功能上与Treg细胞相互抑制,维持机体局部微环境的平衡.本文旨在探讨Th17细胞、Treg细胞在肿瘤免疫中所扮演的不同角色,及Th 17/Treg失衡与肿瘤免疫的关系及作用.     

Th17细胞和Treg细胞与变态反应性气道疾病

变态反应性疾病,如变应性鼻炎、哮喘和遗传性过敏症,都是由于免疫反应失调所引起的。从发现IL-17细胞因子家族以来,通过对IL-23介导的免疫病理反应的研究,证实了Th17是CD4+T细胞的一个亚群,产生IL-17细胞因子。IL-17促进趋化因子、促炎细胞因子和金属蛋白酶的表达,并刺激炎症反应及中     

维生素D类似物对咪喹莫特诱导的银屑病模型小鼠的影响及机制研究

目的探究维生素D类似物钙泊三醇(CAL)对咪喹莫特诱导的银屑病模型小鼠的保护作用以及机制研究。方法构建银屑病模型小鼠,随机分为3组:模型组、钙泊三醇组、雷公藤组,每组10只,另设正常组10只。正常组小鼠于背部暴露处涂抹等量凡士林;模型组于小鼠背部涂抹42 mg 5%咪喹莫特乳膏,连续涂抹1周。钙泊三醇组:模型组基础上涂抹20 g钙泊三醇软膏,1次/d,连续涂抹1周。雷公藤组:灌胃10 mg/kg的雷公藤多苷片,1次/d,连续1周。末次给药后2 d、4 d、8 d、12 d评估小鼠皮肤受损指数(PASI),HE染色观察受损皮肤组织病理形态学;酶联免疫法检测血清中转化生长因子-β(TGF-β)、白细胞介素17A(IL-17A)、白细胞介素4(IL-4)、白细胞介素23(IL-23)水平,流式细胞术分析淋巴液中Th17、CD11c细胞比率;蛋白免疫印迹(WB)以及免疫组化法检测IL-17A、RORrt、IL-23蛋白表达。结果与正常组相比,模型组小鼠PASI评分、血清中TGF-β、IL-17、IL-4、IL-23水平、淋巴液中Th17、CD11c细胞比率、IL-17A、RORrt、IL-23蛋白表达升高(P 0. 05);与模型组相比,钙泊三醇组、雷公藤组小鼠PASI评分、血清中TGF-β、IL-17、IL-4、IL-23水平、淋巴液中Th17、CD11c细胞比率、IL-17A、RORrt、IL-23蛋白表达均降低(P 0. 05)。结论 CAL对银屑病小鼠皮肤受损具有一定的保护作用,其可能与抑制Th17、CD11c以及炎症因子IL-17/IL-23有关。     

PD-L2在小鼠未成熟树突状细胞上的表达及其生物学意义

目的探讨PD-L2分子在小鼠未成熟DCs上的表达及其在T细胞活化中的作用。方法采用GM-CSF和IL-4联合方案体外诱导小鼠髓系DCs,采用FITC-Dextran吞噬实验和3H-TdR掺入试验鉴定未成熟DCs;采用流式细胞术检测未成熟DCs和经抗原负载及TNF-α刺激成熟的DCs上PD-L2、CD80和CD86的表达;混合淋巴细胞反应(MLR)和抗PD-L2单抗阻断试验分析未成熟DCs表达的PD-L2分子对T淋巴细胞的共刺激效应;3H-TdR掺入试验检测未成熟DCs对T淋巴细胞的促增殖效应;ELISA测定各组MLR反应上清中IL-2的分泌水平。结果经GM-CSF和IL-4联合方案体外诱导5～6d天的DCs抗原吞噬能力最强,且CD80和CD86的表达为中等水平,刺激T细胞增殖能力较TNF-α作用48h的DCs显著低下,其可视为未成熟DCs,未成熟和成熟DCs均表达PD-L2分子,但未成熟DCs的表达较为低下,且未成熟DCs表面PD-L2分子可抑制T细胞的增殖,抑制T细胞分泌IL-2。结论PD-L2分子表达在未成熟DCs可通过下调T细胞分泌IL-2介导未成熟DCs免疫不应答效应。     

过继妊娠诱导的CD4+CD25+调节性T细胞治疗不明原因复发性流产

目的 观察过继转输正常妊娠诱导的CD4+CD25+调节性T细胞(CD4+CD25+Treg)对不明原因流产的作用机制及妊娠预后的影响.方法 以雌性CBA/J×雄性BALB/c为正常妊娠模型,以雌性CBA/J×雄性DBA/2J为自然流产模型,磁珠分选雌性CBA/J小鼠脾脏CD4+CD25+Treg细胞并流式细胞术(flow cytometry,FCM)分析细胞纯度.将未孕CD4+CD25+Treg细胞和正常妊娠孕14d的CD4+CD25+Treg分别转输至流产模型孕4d(着床期)的雌性CBA/J孕鼠,于孕14d分别观察宿主孕鼠的胚胎吸收率并测定宿主外周血和母胎界面组织体外培养上清液中Th1Th2/Th3型细胞因子(IFN-γ/TGF-βI/IL-10)水平.结果 与对照组比较,过继转输正常妊娠诱导的CD4+CD25+Treg细胞的宿丰孕鼠的胚胎吸收率(11.32%)显著下降;外周血TGF-β 1/IFN-γ中位数(438)和IL-10/IFN-γ中位数(14)显著增加;母胎界而上TGF-β 1中位数(5899.02pg/mL)和IL-10中位数(158.85pg/mL)显著增加,IFN-γ中位数(18.46 pg/mL)显著下降.结论 孕早期过继转输正常妊娠诱导的CD4+CD25+Treg细胞疗法能诱导宿主母胎免疫耐受并调节细胞因子表达,有利于妊娠维持的Th2、Th3应答偏移.     

肾癌患者外周血Th1/Th2和Tc1/Tc2细胞因子的表达

目的检测不同临床分期肾癌患者外周血CD4+T细胞、CD8+T细胞中细胞因子的表达水平,分析Th1/Th2及Tc1/Tc2漂移对肾癌发生和转移的临床意义。方法用流式细胞仪检测60例不同分期肾癌患者和40例正常对照者外周血CD4+T细胞、CD8+T细胞分泌的IFN-γ、IL-2、TNF-α、IL-4、IL-6和IL-10的表达水平。结果与正常对照组相比,无症状型肾癌患者各细胞因子的表达无明显差异,而局限型患者Th1、Tc1类细胞因子IFN-γ、IL-2和TNF-α分泌水平降低(P<0.01),局部进展型和转移型肾癌患者Th1、Tc1类细胞因子IFN-γ、IL-2和TNF-α分泌水平明显下降(P<0.01);而Th2、Tc2类细胞因子IL-4、IL-6(P<0.05,P<0.01)分泌水平升高。结论 Th1/Th2偏移和Tc1/Tc2偏移促进了晚期肾肿瘤的进展和转移。T淋巴细胞亚群改变导致免疫功能失调,使肿瘤细胞发生免疫逃逸。     

IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4(+)CD45RB(hi)CD25(-) cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell-dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis.     

Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17-producing CD4(+) T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (T(reg) cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of T(reg) cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10-treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4(+) T cells to FOXP3(+) induced T(reg) cells (iT(reg) cells). These results suggest that the defective generation of IL-10-induced tolerogenic DCs and iT(reg) cells may contribute to inflammatory changes in HIES.     

Dendritic cells trigger imbalance of Th1/Th2 cells in silica dust exposure rat model via MHC-II,CD80, CD86 and IL-12

Silicosis is one of the most common occupational respiratory diseases caused by inhaling silica dust over a prolonged period of time, and the progression of silicosis is accompanied with chronic inflammation and progressive pulmonary fibrosis, in which dendritic cells (DCs), the most powerful antigen presentation cell (APC) in the immune response, play a crucial role. To investigate the role of DCs in the development of silicosis, we established an experimental silicosis rat model and examined the number of DCs and alveolar macrophages (AMs) in lung tissues using immunofluorescence over 84 days. Additionally, to obtain an overview of the immunological changes in rat lung tissues, a series of indicators including Th1/Th2 cells, IFN-γ, IL-4, MHC-II, CD80/86 and IL-12 were detected using flow cytometry and an enzyme-linked immunosorbent assay (ELISA) as well as a real-time polymerase chain reaction (PCR) assay. We observed that the number of DCs slightly increased at the inflammatory stage, and it increased significantly at the final stage of fibrosis. Polarization of Th1 cells and IFN-γ expressions were dominant during the inflammatory stage, whereas polarization of Th2 cells and IL-4 expressions were dominant during the fibrotic stage. The subsequent mechanistic study found that the expressions of MHC-II, CD80/86 and IL-12, which are the key molecules that connect DCs and Th cells, changed dynamically in the experimental silicosis rat model. The data obtained in this study indicated that the increase in DCs may contribute to polarization of Th1/Th2 cells via MHC-II, CD80/86, and IL-12 in silica dust-exposed rats.

Dendritic cells (DCs), the most powerful antigen presentation cell (APC) in the immune response, play a crucial role in silicosis.     

A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo

Interferon (IFN)-gamma, a cytokine critical for resistance to infection and tumors, is produced by CD4(+) helper T lymphocytes after stimulation by cultured dendritic cells (DCs) that secrete a cofactor, interleukin (IL)-12. We have identified a major IL-12-independent pathway whereby DCs induce IFN-gamma-secreting T helper (Th)1 CD4(+) T cells in vivo. This pathway requires the membrane-associated tumor necrosis family member CD70 and was identified by targeting the LACK antigen from Leishmania major within an antibody to CD205 (DEC-205), an uptake receptor on a subset of DCs. Another major DC subset, targeted with 33D1 anti-DCIR2 antibody, also induced IFN-gamma in vivo but required IL-12, not CD70. Isolated CD205(+) DCs expressed cell surface CD70 when presenting antigen to T cell receptor transgenic T cells, and this distinction was independent of maturation stimuli. CD70 was also essential for CD205(+) DC function in vivo. Detection of the IL-12-independent IFN-gamma pathway was obscured with nontargeted LACK, which was presented by both DC subsets. This in situ analysis points to CD70 as a decision maker for Th1 differentiation by CD205(+) DCs, even in Th2-prone BALB/c animals and potentially in vaccine design. The results indicate that two DC subsets have innate propensities to differentially affect the Th1/Th2 balance in vivo and by distinct mechanisms.     

In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma

Although dendritic cells (DCs) play an important role in sensitization to inhaled allergens, their function in ongoing T helper (Th)2 cell-mediated eosinophilic airway inflammation underlying bronchial asthma is currently unknown. Here, we show in an ovalbumin (OVA)-driven murine asthma model that airway DCs acquire a mature phenotype and interact with CD4(+) T cells within sites of peribronchial and perivascular inflammation. To study whether DCs contributed to inflammation, we depleted DCs from the airways of CD11c-diphtheria toxin (DT) receptor transgenic mice during the OVA aerosol challenge. Airway administration of DT depleted CD11c(+) DCs and alveolar macrophages and abolished the characteristic features of asthma, including eosinophilic inflammation, goblet cell hyperplasia, and bronchial hyperreactivity. In the absence of CD11c(+) cells, endogenous or adoptively transferred CD4(+) Th2 cells did not produce interleukin (IL)-4, IL-5, and IL-13 in response to OVA aerosol. In CD11c-depleted mice, eosinophilic inflammation and Th2 cytokine secretion were restored by adoptive transfer of CD11c(+) DCs, but not alveolar macrophages. These findings identify lung DCs as key proinflammatory cells that are necessary and sufficient for Th2 cell stimulation during ongoing airway inflammation.     

Regulatory mechanisms of helper T cell differentiation: new lessons learned from interleukin 17 family cytokines

Interleukin 17 (IL-17) family consists of six cytokines in mammals. Among them, IL-17 and IL-17F are expressed by a novel subset of CD4+ helper T (Th) cells and play critical function in inflammation and autoimmunity. On the other hand, IL-17E, also called IL-25, has been associated with allergic responses. Here we summarize recent work by us as well as other investigators in understanding the regulation and function of these three cytokines. From these studies, IL-17 family cytokines may serve as novel targets for pharmaceutical intervention of immune and inflammatory diseases.     

Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells

Langerhans cells (LCs) represent a subset of immature dendritic cells (DCs) specifically localized in the epidermis and other mucosal epithelia. As surrounding keratinocytes can produce interleukin (IL)-15, a cytokine that utilizes IL-2Rgamma chain, we analyzed whether IL-15 could skew monocyte differentiation into LCs. Monocytes cultured for 6 d with granulocyte/macrophage colony-stimulating factor (GM-CSF) and IL-15 differentiate into CD1a(+)HLA-DR(+)CD14(-)DCs (IL15-DCs). Agents such as lipopolysaccharide (LPS), tumor necrosis factor (TNF)alpha, and CD40L induce maturation of IL15-DCs to CD83(+), DC-LAMP(+) cells. IL15-DCs are potent antigen-presenting cells able to induce the primary (mixed lymphocyte reaction [MLR]) and secondary (recall responses to flu-matrix peptide) immune responses. As opposed to cultures made with GM-CSF/IL-4 (IL4-DCs), a proportion of IL15-DCs expresses LC markers: E-Cadherin, Langerin, and CC chemokine receptor (CCR)6. Accordingly, IL15-DCs, but not IL4-DCs, migrate in response to macrophage inflammatory protein (MIP)-3alpha/CCL20. However, IL15-DCs cannot be qualified as "genuine" Langerhans cells because, despite the presence of the 43-kD Langerin, they do not express bona fide Birbeck granules. Thus, our results demonstrate a novel pathway in monocyte differentiation into dendritic cells.     

Complementary dendritic cell-activating function of CD8+ and CD4+ T cells: helper role of CD8+ T cells in the development of T helper type 1 responses

Dendritic cells (DCs) activated by CD40L-expressing CD4+ T cells act as mediators of "T helper (Th)" signals for CD8+ T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4+ T cells, is supported by the complementary DC-activating signals from both CD4+ and CD8+ T cells. Cord blood- or peripheral blood-isolated naive CD8+ T cells do not express CD40L, but, in contrast to naive CD4+ T cells, they are efficient producers of IFN-gamma at the earliest stages of the interaction with DCs. Naive CD8+ T cells cooperate with CD40L-expressing naive CD4+ T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4+ T cell responses. Moreover, the recognition of major histocompatibility complex class I-presented epitopes by antigen-specific CD8+ T cells results in the TNF-alpha- and IFN-gamma-dependent increase in the activation level of DCs and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I-restricted CD8+ T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I-presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections.