CpG DNA对支气管哮喘Th1/Th2类细胞因子调节的研究进展

支气管哮喘（哮喘）发病的重要基础是辅助性T细胞（T helper cell，Th）两种亚型Th1和Th2细胞组成的比例及功能失衡。CpG DNA能抑制嗜酸粒细胞（eosinophils，EOS）的气道浸润，抑制气道变应性炎症，使Th2型细胞因子白介素4（IL-4）产生减少，并诱导Th1型细胞因子白介素12（IL-12）和7干扰素（IFN-γ）产生，诱导Th1反应，下调Th2反应，使Th2反应向Thl反应转变，进而使Th1／Th2细胞比例和功能达到平衡的状态，在哮喘治疗中具有重要的意义。     

Th17与慢性气道炎症性疾病

最近的研究发现了一种新的活化的CD4^＋T细胞亚群——Thl7细胞亚群，它在慢性气道炎症性疾病的发生发展中发挥着重要的作用。Thl7细胞亚群分泌产生的细胞因子IL-17可以通过诱导趋化因子CXCL8（IL-8）的释放，促进气道内中性粒细胞募集和激活，与慢性气道炎症性疾病的气道重塑密切相关。另外，Thl7细胞亚群是一个与Thl和Th2细胞亚群不同的独立的分支，其分化不依赖于调节传统的Thl和Th2细胞亚群分化的细胞因子和转录因子。鉴于Thl7细胞及其细胞因子在气道重塑及慢性气道炎症中的重要作用，本文就Thl7与慢性气道炎症性疾病的研究作一综述：     

鼠白细胞介素12基因治疗对支气管哮喘小鼠CD44和CD49d表达的影响

白细胞介素12（IL-12）能促进Th1细胞分化，抑制Th2细胞分化，纠正支气管哮喘（简称哮喘）发病中的Th1／Th2失衡。但长期体内直接应用IL-12重组蛋白可引起严重的不良反应。因此将IL-12基因以质粒为载体导人体内，使之产生内源性的IL-12而达到抑制炎症的作用，在哮喘的防治中具有一定的理论和实际意义。小鼠IL-12质粒（mIL-12质粒）对哮喘气道炎症和细胞因子的影响研究已经获得初步结果，     

细胞因子与过敏性哮喘

支气管哮喘是一种慢性气道炎症性疾病。在气道炎症反应中，无论是Th2型细胞因子（IL-4、IL-5、IL-13等），还是Th1型细胞因子IFN-γ均起着重要作用。新近研究进一步表明调节性T细胞（Treg）产生的细胞因子也与过敏性哮喘的发病密切相关。     

Th2／Th17细胞群与支气管哮喘机制研究

支气管哮喘（简称哮喘）是一种由多种细胞（如嗜酸粒细胞、肥大细胞、T淋巴细胞、中性粒细胞和气道上皮细胞等）和细胞组分参与的气道慢性炎症性疾病。经典的Th1／Th2细胞失衡被认为是过敏性哮喘的主要发病机制,Th17／IL-17轴被证实与重症哮喘、激素抵抗型哮喘、以中性粒细胞浸润为主的哮喘有关。近年来研究发现,机体内存在一种不同于目前已知的Thl、Th2、Thl7、Th9等的新型CD4＋T细胞,被称为Th2／Th17双表型记忆性CD4＋T细胞群（简称Th2／Th17细胞群）。在哮喘发病机制的探讨中发现,Th2／Th17细胞群既能分泌Th2表型细胞因子IL-4、IL-5、IL-13,也可以分泌Th17型细胞因子IL-17、IL-8、IL-22等;且在不同的微环境下发生不一样的生物学效应,这显示了Th2／Th17细胞群可能在哮喘发生发展（特别是重症哮喘）及各亚型相互转化过程中起着决定性作用。现就Th2／Th17细胞群的生物学功能及其与哮喘的相关性进行如下综述。     

IL-12/IL-13失衡与支气管哮喘

白介素（IL）-12和IL-13对支气管哮喘的异常免疫起了关键作用。IL-12具有调节Th1/Th2细胞免疫应答的作用，哮喘患者由于IL-12产生缺陷而导致Th2细胞免疫应答过强；IL-13作为Th2型细胞因子成员，通过激活嗜酸粒细胞，减少其凋亡，促进IgE分泌等机制，广泛参与过敏性哮喘及炎症疾病过程。充分证据表明这两种关键性免疫调节细胞因子在哮喘患者的肺中产生不平衡，即IL-13过量产生和IL-12产生减少。IL-12/IL-13产生失衡是哮喘发病的关键因素之一，如何调整两者的平衡是哮喘治疗的一个方向。     

T细胞在哮喘免疫调节中的作用

哮喘是由T细胞、嗜酸粒细胞、肥大细胞等多种炎症细胞参与的气道慢性炎症性疾病,气道慢性炎症导致气道高反应性(AHR)的形成。其中Th2细胞通过分泌IL-4、IL-5、IL-9、IL-13等多种细胞因子在哮喘发病中起主要作用,而Th1分泌的IFN-γ抑制Th2的功能,近年来研究发现CD4+T细胞还包括多种具有调节功能的细胞群体并参与哮喘的免疫调节。另外,NKT细胞和CD8+T细胞在哮喘免疫调节中亦具有一定的作用。1Th1/Th2与哮喘1986年,Mossmann等[1]发现小鼠CD4+T存在Th1和Th2两个亚群,Th1产生白介素-2(IL-2)、干扰素(IFN)γ和β,不产生IL-4和IL…     

T细胞在哮喘免疫调节中的作用

哮喘是由T细胞、嗜酸粒细胞、肥大细胞等多种炎症细胞参与的气道慢性炎症性疾病,气道慢性炎症导致气道高反应性（AHR）的形成.其中Th2细胞通过分泌IL-4、IL-5、IL-9、IL-13等多种细胞因子在哮喘发病中起主要作用,而Th1分泌的IFN-γ抑制Th2的功能,近年来研究发现CD4^＋T细胞还包括多种具有调节功能的细胞群体并参与哮喘的免疫调节.另外,NKT细胞和CD8^＋T细胞在哮喘免疫调节中亦具有一定的作用.     

信号转导子和转录激活子6、过氧化物酶体增殖，活化体受体-γ与支气管哮喘

Th1／Th2细胞比例失调和Th2细胞优势分化是支气管哮喘发病的主要机制。信号转导子和转录激活子6（STAT6）是Th2细胞特异性转录因子，被IL-4等激活后诱导相关炎症基因的表达：STAT6信号通路在支气管哮喘气道炎症和高反应性中起重要作用。过氧化物酶体增殖活化体受体-γ（PPAR-γ）可通过抑制炎症信号通路，减轻气道炎症并抑制气道重构等。本文综述了STAT6在哮喘炎症中的作用及PPAR-γ对支气管哮喘炎症等方面的影响，为哮喘的临床治疗提供新的思路。     

GATA-3基因反义逆转录病毒载体的构建

支气管哮喘(简称哮喘)是一种呼吸道慢性炎症性疾病。Ⅱ型辅助性T淋巴细胞(Th2)在起始和维持气道慢性炎症级联反应中具有重要作用。GATA-3为Th2淋巴细胞特异性转录因子，在Th2淋巴细胞分化及Th2类细胞因子基因转录中具有关键性作用^[1]。我们的实验应用反义真核表达载体构建技术，构建了GATA-3反义逆转录病毒载体．对进一步研究Th2淋巴细胞定向分化及Th2类细胞因子基因转录的分子机制和探讨哮喘治疗的新途径均具有重要意义。     

Immunomodulation in the treatment and/or prevention of bronchial asthma

The immunologic hallmark of atopic allergy and asthma is an increased production of IgE and T helper (h) type 2 cell cytokines (interleukin (IL)-4, IL-5, IL-9 and IL-13) by Th cells reacting to common environmental allergens. All of us inhale allergens and healthy non-atopics produce allergen-specific IgG1, IgG4 and the Th1 cytokine interferon-α, as well as IL-12 from macrophages. We now have many modalities of immunomodulation to decrease the effect of IL-4 or IL-5 or production and level of IgE or agents to shift the immune response from a Th2 to a Th1 response, thereby decreasing the allergic inflammatory response in the airways. In the present review we focus on conventional immunotherapy, mycobacterial vaccines, DNA vaccines using cytosine guanosine, inhibitors of IL-4 and IL-5 and anti-IgE: Omalizumab.     

IL-33/ST2轴在呼吸道病毒感染免疫中的作用

IL-33是 IL-1家族的新成员,它能通过结合 IL-1受体家族中的孤儿受体 ST2发挥其生物学效应。很多研究证实呼吸道病毒感染可刺激机体多种细胞显著表达及分泌 IL-33,IL-33作用于靶细胞表面 ST2受体,从而启动 T 辅助细胞(T helper,Th)2型免疫反应,介导呼吸道病毒感染相关疾病。抗 IL-33抗体或抗 ST2抗体阻断 IL-33/ST2轴及上述免疫反应,从而有可能为治疗呼吸道病毒感染相关疾病提供新靶点。     

Interferon-gamma increases IL-12 mRNA expression and attentuates allergic late-onset airway responses in the Brown Norway rat.

Interferon gamma is a T-helper cell (Th)-1-type cytokine that has been suggested to inhibit the development of an atopic Th2-type profile of cytokine expression. The aim of this study was to investigated the effect of exogenous rat interferon gamma on antigen-induced airway responses, and on Th1 and Th2-type cytokine messenger ribonucleic acid (mRNA) expression in the Brown Norway rat. Rats were actively sensitized to ovalbumin and 14 days later underwent an aerosolized ovalbumin challenge. Animals were intratracheally administered either interferon gamma (3,000 U) or control solvent 30 min prior to, and 2 and 4 h following, antigen challenge. Lung resistance was monitored over an 8-h time period. Using in situ hybridization and immunocytochemistry, the levels of Th1- (interleukin-12) and Th2-type (interleukin4 and -5) cytokine mRNA, and major basic protein expression in the bronchoalveolar lavage fluid of these rats 8 h after ovalbumin challenge were also determined. Administration of interferon gamma attenuated the development of the late-onset airways response in ovalbumin-sensitized antigen-challenged rats (p<0,05). The expression of interleukin-4 and -5 mRNA in the bronchoalveolar lavage fluid of interferon gamma treated rats was significantly attenuated compared to ovalbumin-challenged saline-treated controls (p<0.001). This was accompanied by a significant increase in the expression of interleukin-12 mRNA, and a reduction in eosinophil numbers. Intratracheal administration of interferon gamma modulates the allergic late-onset airways response in rats, and this is associated with a reduction in the expression of T-helper cell 2-type cytokines and an increase in interleukin-12 messenger ribonucleic acid expression within the airways. The present results support a role for interferon gamma in the pathophysiology of acute allergic airway responses, possibly by virtue of its ability to modulate T-helper cell 1- 2-type cytokine expression within the lungs.     

Th9与支气管哮喘

支气管哮喘（简称哮喘）是一种由多种细胞如淋巴细胞、嗜酸粒细胞、肥大细胞等及其细胞组分参与的气道慢性炎症疾患,Th2细胞被认为是哮喘发病机制中的主要效应细胞。长期以来,白介素9（IL-9）都被认为是Th2类细胞因子,在变应性疾病,尤其是过敏性哮喘、变应性鼻炎等发病机制中起着重要的作用。近年来研究发现,机体内可能存在着一群新型的不同于目前已知Th1、Th2及Th17等效应细胞,被称之为＂Th9＂细胞。Th9细胞在转化生长因子-β及IL-4联合刺激下分化而来,具有分泌IL-9和IL-10的能力。Th9细胞作为效应性T细胞,在促进组织炎症发生的过程中起着重要作用。现就Th9细胞的生物学功能及与哮喘的关系进行简要综述。     

Roxithromycin specifically inhibits development of collagen induced arthritis and production of proinflammatory cytokines by human T cells and macrophages

OBJECTIVE: Roxithromycin (RXM) is a macrolide antibiotic that is effective in treatment of chronic lower respiratory tract diseases including diffuse panbronchiolitis and bronchial asthma. Its mechanism of action apart from its antibacterial action remains unclear. To determine the mechanism of action of RXM, we evaluated the effect of RXM on T cell functions and the inflammatory responses in mice with collagen induced arthritis (CIA). METHODS: T cell proliferation, cytokine production by T cells stimulated through CD28, CD26, or PMA with or without anti-CD3 Mab, cytokine production by macrophages stimulated with lipopolysaccharide, and transendothelial migration of T cells were analyzed in the presence or absence of various concentrations of RXM. We evaluated the effect of RXM treatment in collagen induced arthritis in mice. RESULTS: RXM did not affect the production of Th1-type and Th2-type cytokines, whereas it specifically inhibited production of proinflammatory cytokines such as tumor necrosis factor-a and interleukin 6 (IL-6) by T cells and macrophages. RXM inhibited T cell migration. We found that RXM treatment of mice with CIA reduced the severity of arthritis and serum level of IL-6, as well as leukocyte migration into the affected joints and destruction of bones and cartilage. CONCLUSION: Our findings strongly suggest that RXM may be useful for the therapy of rheumatoid arthritis as well as other inflammatory diseases such as Crohn's disease.     

The IL-23/IL-17 pathway in inflammatory bowel disease

The etiology of inflammatory bowel disease is unknown but available evidence suggests that a deregulated immune response towards the commensal bacterial flora is responsible for intestinal inflammation in genetically predisposed individuals. IL-23 promotes expansion and maintenance of Th17 cells, which secrete the proinflammatory cytokine IL-17 and have been implicated in the pathogenesis of many chronic inflammatory disorders. Recent studies have shown that IL-23 also acts on cells of the innate immune system that can contribute to inflammatory cytokine production and tissue inflammation. A role for the IL-23/IL-17 pathway in the pathogenesis of chronic intestinal inflammation in inflammatory bowel disease has emerged from both animal and human studies. Here we aim to review the recent advances in this rapidly moving field.     

Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice.

Helper T (Th) cells are classified as Th1 or Th2 cells by virtue of cytokine secretion and function as mediators of cellular or humoral immunity, respectively. Cytokines also regulate the differentiation of Th cells. For example, interleukin (IL)-12 promotes Th1 and suppresses Th2 cell development, suggesting that IL-12 may be useful therapeutically in Th2-mediated autoimmune and allergic disorders. Therefore, the effect of systemic IL-12 treatment on in vivo autoantibody synthesis in hepatitis B e antigen (HBeAg)-expressing transgenic mice, which is dependent on self-reactive Th2 cells, was examined. Low-dose IL-12 significantly inhibited autoantibody production by shifting the Th2-mediated response toward Th1 predominance. Additionally, previous studies suggest that a predominance of HBeAg-specific Th2-type cells may contribute to chronicity in hepatitis B virus infection. Therefore, IL-12 may also prove beneficial in modulating the HBeAg-specific Th response to favor viral clearance in chronic hepatitis B virus infection.     

Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway

Graft rejection has been defined as the mirror image of graft-versus-host disease, which is biologically characterized primarily as a Th1-type process. As such, we reasoned that graft rejection would represent a Th1 response amenable to Th2 modulation. Indeed, adoptive transfer of host Th1-type cells mediated rejection of fully MHC-disparate murine bone marrow allografts more effectively than host Th2-type cells. Furthermore, STAT1-deficient host T cells did not differentiate into Th1-type cells in vivo and failed to mediate rejection. We next hypothesized that donor Th2 cell allograft augmentation would prevent rejection by modulation of the host Th1/Th2 balance. In the setting of donor Th2 cell therapy, host-anti-donor allospecific T cells acquired Th2 polarity, persisted posttransplantation, and did not mediate rejection. Abrogation of rejection required donor Th2 cell IL-4 secretion and host T-cell STAT6 signaling. In conclusion, T cell-mediated marrow graft rejection primarily resembles a Th1-type process that can be abrogated by donor Th2 cell therapy that promotes engraftment through a novel mechanism whereby cytokine polarization is transferred to host T cells.     

Ribavirin or CpG DNA sequence-modulated dendritic cells decrease the IgE level and airway inflammation

Asthma is an allergic disease that is characterized by the imbalance between Th1 and Th2 cells and by the predominant Th2-type immune response. In this study, we investigated the application of dendritic cell (DCs)-based immunotherapy in modulating the immune response of allergic diseases. DCs incubated with ovalbumin (OVA), OVA plus ribavirin, OVA plus CpG-oligodeoxynucleotides (ODN 1826), or OVA plus non-CpG-ODN (ODN 1745) for 48 hours were injected intravenously into four corresponding groups of BALB/c mice. All of the mice were then immunized with OVA intraperitoneally 7 days later to establish an animal model of asthma. Serum levels of OVA antibody, airway hyperresponsivness, cell composition and cytokine levels in the bronchoalveolar lavage fluid, and cytokine profiles of spleen cells were analyzed. The data showed that ribavirin and ODN 1826 increased interleukin-12 synthesis and inhibited interleukin-10 production. ODN 1826 could also enhance the expression of B7.1, B7.2, major histocompatibility complex I, and major histocompatibility complex II molecules. Furthermore, the DCs modulated by ribavirin and ODN 1826 could downregulate the Th2-type immune response in vivo and could alleviate airway inflammation. This study elucidated the effect of ribavirin and CpG-ODN on DCs and demonstrated that in vitro modulated DCs might be a potential therapeutic approach for asthma.     

Th9与支气管哮喘

支气管哮喘(简称哮喘)是一种由多种细胞如淋巴细胞、嗜酸粒细胞、肥大细胞等及其细胞组分参与的气道慢性炎症疾患,Th2细胞被认为是哮喘发病机制中的主要效应细胞.长期以来,白介素9(IL-9)都被认为是Th2类细胞因子,在变应性疾病,尤其是过敏性哮喘、变应性鼻炎等发病机制中起着重要的作用.近年来研究发现,机体内可能存在着一群...