Serum Th1 and Th2 cytokine balance in patients of superficial transitional cell carcinoma of bladder pre- and post-intravesical combination immunotherapy

Combination therapy with intravesical bacillus Calmette-Guerin (BCG) plus interferon-α2b (IFN-α2b) for superficial transitional cell carcinoma (TCC) seems to be immune-dependent and activation of Th1 immune response is required for clinical efficacy. The present study evaluates circulating serum cytokine profiles (Th1/Th2 cytokines IFN-γ, IL-2 TNF-α, IL-4, IL-6 and IL-10) in 41 bladder cancer patients prior to transurethral resection of tumor (TURBT) (pre-therapy), and following intravesical combination immunotherapy (post-therapy) and their association with recurrence. Mean levels of IL-2 and TNF-α were significantly reduced while IL-4, IL-6 and IL-10 were significantly enhanced in pre-therapy samples as compared to controls. Mean levels of IFN-γ, IL-2 and TNF-α were significantly increased while IL-4 and IL-10 were significantly reduced in patients after instillation of combination immunotherapy. These findings suggest that bladder cancer patients develop Th2 dominant status with deficient type 1 immune response that shows tendency to reversal following therapy.     

急性MCMV感染对小鼠脾Th1/Th2/Th17细胞亚群分化的影响

目的:在整体水平观察小鼠巨细胞病毒(MCMV)感染对小鼠脾Th1/Th2/Th17细胞亚群分化及其主要的效应性细胞因子(IFN-γ、IL-4、IL-17A)表达的影响.方法:建立MCMV感染模型,8只BALB/c小鼠分别于接种MCMV Smith株后3天和14天各处死4只;另设8只接种唾液腺匀浆的模拟感染小鼠作为对照.用空斑形成试验测定肝、脾和唾液腺组织病毒滴度;流式细胞术检测脾T淋巴细胞中Th1(CD4+ IFN-γ+)、Th2(CD4+ IL-4+)、Th17(CD4+IL-17A+)细胞比例,双抗体夹心ELISA法检测脾细胞培养上清中病毒特异性IFN-γ、IL-4、IL-17A水平.结果:MCMV感染早期肝、脾和唾液腺组织中病毒呈低水平复制,而感染后14天仅在唾液腺组织呈高水平复制;Th1细胞比例及病毒特异性IFN-γ主要在MCMV感染早期呈显著升高(P ＜0.01);Th2细胞及IL-4均无明显表达及改变;Th17细胞及病毒特异性IL-17A则主要在感染后14天升高(P＜0.05).结论:MCMV感染早期,机体通过上调Th1细胞分化比例及IFN-γ的表达发挥抗病毒效应,而MCMV诱导Th17细胞分化及IL-17A的高表达可能是MCMV感染致宿主特异性细胞免疫功能失调并逃避机体特异性细胞免疫攻击的原因之一.     

NK cells modulate the lung dendritic cell‐mediated Th1/Th17 immunity during intracellular bacterial infection

The impact of the interaction between NK cells and lung dendritic cells (LDCs) on the outcome of respiratory infections is poorly understood. In this study, we investigated the effect and mechanism of NK cells on the function of LDCs during intracellular bacterial lung infection of Chlamydia muridarum in mice. We found that the naive mice receiving LDCs from C. muridarum‐infected NK‐cell‐depleted mice (NK‐LDCs) showed more serious body weight loss, bacterial burden, and pathology upon chlamydial challenge when compared with the recipients of LDCs from infected sham‐treated mice (NK+LDCs). Cytokine analysis of the local tissues of the former compared with the latter exhibited lower levels of Th1 (IFN‐γ) and Th17 (IL‐17), but higher levels of Th2 (IL‐4), cytokines. Consistently, NK‐LDCs were less efficient in directing C. muridarum‐specific Th1 and Th17 responses than NK+LDCs when cocultured with CD4⁺ T cells. In NK cell/LDC coculture experiments, the blockade of NKG2D receptor reduced the production of IL‐12p70, IL‐6, and IL‐23 by LDCs. The neutralization of IFN‐γ in the culture decreased the production of IL‐12p70 by LDCs, whereas the blockade of TNF‐α resulted in diminished IL‐6 production. Our findings demonstrate that NK cells modulate LDC function to elicit Th1/Th17 immunity during intracellular bacterial infection.     

Th1/Th2失衡及毛细支气管炎特异性免疫治疗的研究进展

毛细支气管炎是婴幼儿时期常见的以喘息为主要表现的下呼吸道疾病.研究毛细支气管炎的免疫学改变及治疗是近年的研究热点,它有助于深入认识毛细支气管炎发生、发展及演变为哮喘的机制,为毛细支气管炎提供新的防治措施.毛细支气管炎患儿存在Th1/Th2失衡的免疫学改变,调节Th1/Th2平衡的免疫治疗是今后毛细支气管炎治疗的新方向.     

Toll样受体与Th1和Th2型免疫应答

Toll样受体是广泛表达在哺乳动物细胞表面的跨膜信号传导受体,其通过识别多种类型的病原体相关分子模式及一些内源性配体,激活天然免疫系统,同时通过诱导树突状细胞分化成熟,调控获得性免疫反应的建立。大多数TLRs的配体可诱导机体产生Th1型免疫应答,然而在某些条件下也可导致Th2型免疫应答的发生。弄清TLRs参与调节Th0分化的机制,可为今后在感染免疫、自身免疫、超敏反应等方面进行深入研究及相关疾病的治疗提供新的切入点。     

Interleukin-12/T cell stimulating factor,a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells

At least two subsets of CD4⁺ T helper cell lymphocytes termed T_h1 and T _h, 2 exist in the mouse and probably in humans. They are characterized by the secretion of different lymphokines and by their functional behavior. Dysregulated expansion of one or the other subset may be one reason for the development of certain diseases. Thus, it is of importance to define the signals involved in the differentiation and activation of the two T_h cell subsets. It is known and has been confirmed in this report that the cytokine interleukin (IL)-1 acts onT_h2 cells but not on T_h1 cells. We now report that a previously identified cytokine which was provisionally termed T cell stimulating factor is identical with IL-12 and exhibits a reciprocal behaviour to IL-1. IL-12 has several effects on T_h1 cells. It can induce the proliferation of certain T_h1 cells in combination with IL-2. Synthesis of interferon (IFN)-γ by T_h1 cells can be triggered by IL-2 plus IL-12. In contrast to the IFN-γ production observed after T cell receptor (TcR) CD3 stimulation of T_h1 cells with lectin Concanavalin A the IFN-γ production induced by IL-12+IL-2 is insensitive to the immunosuppressive drug cyclosporin A. Furthermore, IL-12 enhances the TcR/CD3-induced synthesis of IFN-γ of several T_h1 clones. Finally, IL-12 (+ IL-2) induces homotypic cell aggregation of T_h1 clones. This type of cell aggregation depends on the participation of LFA-1 and ICAM-1 molecules. In all activation systems with T_h1 cells no effect of IL-1 was demonstrable. In contrast, only IL-1 but not IL-12 served as a co-stimulatory signal for several T_h2 cell lines activated via the TcR/CD3 complex.     

三种类型肺癌患者外周血Th1/Th2相关细胞因子的临床分析

目的：了解不同病理类型肺癌患者辅助性T细胞亚群（Th1/Th2）的反应状态,探讨肺癌发生发展的免疫机制。方法：收集三种不同病理类型肺癌患者47例（鳞癌23例,腺癌15例,小细胞肺癌9例）、健康志愿者31例的血清,分成肺癌组、正常对照组,用酶联免疫吸附试验（ELISA）检测各组外周血中Th1型细胞因子、白细胞介素2（IL-2）、γ-干扰素（IFN-γ）和Th2型细胞因子IL-4、IL-10的浓度。结果：三种不同病理类型肺癌患者外周血中IL-2、IFN-γ浓度均显著低于正常人组,IL-4、IL-10浓度显著高于正常人组（P〈0.05）。结论：腺癌、鳞癌、小细胞非分化癌三种不同病理类型的肺癌患者外周血中的免疫细胞均呈现Th2型免疫反应优势状态,呈现Th1/Th2的漂移状态。     

Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck

Levels of cytokines, and in particular those that reflect Th1 or Th2 bias, were measured in the plasma of patients with head and neck squamous cell carcinomas (HNSCC). Compared with plasma cytokine levels of age-matched controls, cytokine levels in HNSCC patients suggested a shift to a Th2 bias as levels of the Th2 cytokines interleukin-4 (IL-4), IL-6, and IL-10 were increased, and levels of the Th1 cytokine interferon-γ (IFN-γ) were decreased. However, levels of the Th1 cytokines IL-2 and granulocyte macrophage–colony-stimulating factor (GM-CSF) were increased, which is not consistent with full Th2 skewing. Assessment of cytokine levels in patients with malignancies other than HNSCC demonstrated many similarities to HNSCC patients, but HNSCC patients exhibited a more pronounced increase in GM-CSF levels and a decline in IFN-γ levels. For most cytokines there was no association between the shifts in cytokine levels in HNSCC patients and either the extent of tumor burden or extent of metastasis. However, patients with large HNSCC tended to be the population that demonstrated increased levels of IL-4 and IL-6. These results suggest skewing toward a Th2 bias in HNSCC patients, with the Th2 shift being incomplete and indicative of the presence, rather than the extent, of malignant disease.     

不明原因习惯性流产患者Th1/Th2型细胞因子的检测

目的 :了解不明原因习惯性流产 (UHA)患者对滋养细胞抗原刺激产生Th1、Th2型细胞因子的水平 ,探讨其在UHA发病中的作用。方法 :选取 5 4例UHA患者 ,35例为未妊娠者 ,为UHA未孕组 ,19例为有UHA病史 ,现在确定妊娠并难免流产者 ,为UHA难免流产组。分别选取 15例正常未孕妇女及正常妊娠者作为对照组。应用酶联免疫吸附法检测未孕各组经滋养细胞抗原刺激的外周血单个核细胞 (PBMC)及妊娠各组PBMC与蜕膜单个核细胞 (DMC)培养上清液中IL 2、IFN γ、IL 4、IL 10的水平。结果 :①在最佳诱导时间下 ,UHA未孕组PBMC产生IL 2、IFN γ的水平明显高于正常未孕组 (P均 <0 0 5 ) ,而IL 4、IL 10水平明显低于正常未孕组 (P均 <0 0 5 )。②UHA难免流产组PBMC及DMC产生的IL 2、IFN γ水平均明显高于正常妊娠组 (P均 <0 0 5 ) ,而IL 4、IL 10水平则明显低于正常妊娠组 ,差异均有显著性 (P均 <0 0 5 )。两组PBMC产生的各细胞因子水平均低于同组DMC ,差异有显著性 (P <0 0 5 )。结论 :UHA患者对滋养细胞抗原产生以Th1型反应为主的免疫应答 ,产生大量Th1型细胞因子 ,导致妊娠丢失。     

在单个细胞水平上分析抗原特异性Th1/Th2细胞因子产生的关联性

目的　在单个细胞水平上 ,观察抗原特异性Th1和Th2细胞因子产生的关联性 ,为进一步阐明CD4 T细胞的分化 ,细胞因子产生的相互关系及其特征提供理论依据。方法　从OVA TCR转基因小鼠的脾和淋巴结中分离CD4 T细胞 ,在体外在抗原提呈细胞存在下 ,用卵白蛋白 (OVA)抗原多肽刺激 3d后 ,再以同样的培养条件刺激 5～ 6h ,固定细胞 ,然后进行细胞表面和细胞内细胞因子染色 ,最后利用流式细胞仪在单个细胞水平上分析Th1和Th2细胞因子产生的关联性。结果　抗原特异性CD4 T细胞经抗原再一次刺激后 ,分泌Th1(IFN γ和IL 2 )和Th2 (IL 4、IL 5和IL 10 )细胞因子。IL 12促进IFN γ的表达 ,控制Th2细胞的分化。此外 ,大多数抗原特异性CD4 T细胞只产生 1种细胞因子 ,1个细胞同时产生 2种细胞因子极少见。结论　在单个细胞水平上的研究结果表明 ,经抗原短暂刺激后 (3d) ,不同的CD4 T细胞亚群只产生 1种Th1和 或Th2细胞因子 ,同时产生两种以上者占有很低的比率     

自体树突状细胞诱导TDLN细胞对胃癌细胞系KATO3的体外杀伤作用

目的：研究用冻融的自体胃癌抗原冲击树突状细胞(DC)来诱导肿瘤引流区淋巴结(TDLN)细胞对胃癌细胞系的体外杀伤作用。方法：采用胃癌患者外周血粘附细胞(PBAC)，经GM-CSF、IL-4、TNF-α诱导和自体肿瘤冻融抗原(Ag)刺激诱生所获得的DC与TDLN细胞1：50比例共培养3天，获得DC激活的TDLN，即DC-TDLN作效应细胞；分别以Ag和培液代替DC同样培养TDLN，即Ag-TDLN和TDLN作对照，对胃癌细胞系KATO3和黑色素瘤细胞系A375进行杀伤。结果：DC-TDLN、Ag-TDLN、TDLN各组细胞对KATO3，均有显著杀伤活性，其中DC-TDLN组的杀伤作用明显优于后两组，且效靶比20：1的杀伤率优于10：1，显示可能有量效关系；而TDLN各组不同效靶比对A375杀伤率则无显著差异。结论：自PBAC获得的DC，经自身肿瘤Ag冲击并与自身TDLN共培养，可使后者对胃癌细胞系细胞的杀伤作用明显增强。     

ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma

ST2 is a member of the IL-1 receptor family and IL-33 was recently identified as its natural ligand. The IL-33/ST2 pathway regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions, but the role of ST2 signaling in tumor growth and metastasis has not been investigated. We aimed to investigate whether ST2 gene deletion affects tumor appearance, growth, and metastasis, and antitumor immunity in an experimental metastatic breast cancer model. Deletion of ST2 in BALB/c mice bearing mammary carcinoma attenuated tumor growth and metastasis, which was accompanied by increased serum levels of IL-17, IFN-γ, and TNF-α and decreased IL-4. Tumor-bearing ST2-/- mice had significantly higher percentages of activated CD27high CD11bhigh NK cells, CD69+ and KLRG- NK cells and higher cytotoxic activity of splenocytes, NK cells, and CD8+ T cells in vitro. A significantly higher number of NK cells expressing IFN-γ were found in ST2-/- mice compared with WT recipients. In vivo depletion of CD8+ or NK cells revealed a key role for NK cells in enhanced antitumor immunity in ST2-/- mice. We report for the first time that suppressed breast cancer progression and metastasis in mice lacking ST2 corresponds mainly with enhanced cytotoxic activity of NK cells, and increased systemic Th1/Th17 cytokines.     

用糖基化磷脂酰肌醇B7-1锚定肿瘤细胞膜进行免疫治疗

目的 研制抗肿瘤免疫治疗的新疫苗.方法 用蛋白转化法将B7-1锚定在肿瘤细胞膜上,免疫C57BL-6小鼠后,一组小鼠取脾细胞进行T细胞扩增和细胞毒T淋巴细胞(CTL)功能检测,另一组小鼠进行肿瘤细胞接种试验.结果 用GPI-B7-1修饰的肿瘤细胞膜免疫小鼠后诱发了肿瘤特异性T细胞扩增和CTL.且该疫苗有一定的保护小鼠免受肿瘤细胞侵袭的作用.结论 GPI蛋白转化法为人类抗肿瘤免疫治疗提供了新的、有效的修饰肿瘤细胞膜的方法.     

Th17细胞与Th1、Treg细胞关系的研究进展

CD4~+T细胞在不同细胞因子环境中可分化为Th1、Th2、Treg、Th17四种亚群,在一定条件下,各Th细胞亚群之间可以互相转化,从而使机体的免疫效应和免疫抑制处于精细而复杂的平衡状态。Th17细胞与自身免疫性疾病和肿瘤的发生发展关系密切,研究Th17细胞与Th1细胞、Treg细胞之间的相互关系,对于预防和治疗自身免疫性疾病和肿瘤等临床难题意义重大。     

树突细胞与哮喘Th1/Th2失衡

特应性哮喘患者以Th2免疫反应为主,导致气道炎症,Th1／Th2失衡是特庆性哮喘重要的免疫病理机制,树突细胞（DCs）中肺部主要抗原递呈细胞,不但可以介志对吸入抗原初始的免疫反应,活化辅助性T细胞,而且在可以决定T细胞的分化方向,维持哮喘Th2免疫反应和Th1／Th2失衡机制中发挥重要作用而日益受到重视。本文就近年来对特应性哮喘免疫病理机制中DCs对Th1／Th2失衡影响认识作一综述。     

Type I interferons and the Th1/Th2 paradigm

During the past year significant advances have been made in our understanding of the factors contributing to the differentiation of CD4⁺ T helper cell subsets. These have been driven, in part, by the realization that cytokines from the innate immune response, such as interleukin-12 (IL-12) and interferons (IFNs), play a critical role in T cell subset differentiation. This review covers some of the most recent data concerning the divergent role that IFNs have in the differentiation of human versus mouse T helper cell subsets. In this review we discuss the molecular basis for the specie-specific effect of type I IFN on the selective induction of Th1 type immune responses. Furthermore, since IFN-β is used in the treatment of multiple sclerosis (MS) we discuss the potential effects of such treatment and the value of the Th1/Th2 paradigm in MS.