变应性鼻炎患者血清IL-17和IL-23的表达及临床意义

目的:检测变应性鼻炎(Allergic rhinitis,AR)患者血清IL-17和IL-23的表达水平并探讨其临床意义。方法:检测25例AR患者(观察组)血清IL-17、IL-23、s Ig E(过敏原特异性Ig E)的表达水平,并以23名健康体检合格者(对照组)为对照,比较两组人群血清中IL-17、IL-23、s Ig E表达水平的差异,并探讨AR患者血清中IL-17、IL-23、s Ig E三者间的相互关系。结果:观察组患者血清中IL-17、IL-23及s Ig E水平均高于对照组(P均0.01);观察组患者血清中IL-17、IL-23、s Ig E三者两两之间均呈线性正相关关系(P均0.05)。结论:IL-17、IL-23参与了AR的发生发展过程,与s Ig E的形成可能有关。     

调节性T细胞在变应性鼻炎免疫应答中的作用

调节性T(Treg)细胞是CD4+T细胞的一个小而关键的亚群,具有维持免疫稳态的作用,诸多研究已证明Treg在过敏性气道疾病中具有巨大的治疗潜力,在免疫抑制和炎症气道的恢复中起至关重要的作用。在变应性鼻炎（AR）中,Treg可抑制第2组先天淋巴细胞、辅助性T细胞、肥大细胞、树突状细胞、嗜酸性粒细胞和B细胞,从而维持耐受性机制。本综述回顾总结了目前关于Treg在AR中如何调节过敏原引发的免疫应答和维持耐受性机制,对充分利用Treg生物学知识为临床防治AR提供重要参考。     

IL-35及其诱导产生的新型调节性T细胞——iTR35细胞

调节性T细胞(Treg)诱导的免疫逃逸机制是肿瘤发生的关键因素之一.IL-35是一种新发现的主要来源于Treg的抑制性细胞因子,其不仅可以作为Treg的重要效应分子直接参与免疫调节,还可以诱导产生一种新型Foxp3Treg——iTR35细胞,从而在肿瘤免疫逃逸过程中级联放大Treg的免疫调节作用,成为进一步促进肿瘤发展和影响抗肿瘤治疗的重要因素.     

IL-23 在变应性鼻炎小鼠模型中的作用及机制的研究

目的:探讨IL-23 在变应性鼻炎小鼠模型中的作用及机制的研究。方法:应用卵清蛋白(OVA)致敏建立小鼠变应性鼻炎模型,给予抗IL-23p19 单克隆抗体干预,计量抗原激发后小鼠搔鼻数量。应用HE 染色方法检测IL-23 对小鼠鼻黏膜炎症影响,应用ELISA 法检测小鼠灌洗液中IL-4、IFN-β及IL-17A 含量。应用PCR 方法检测鼻黏膜中FOXP3 的含量。结果:治疗后抗IL-23p19 抗体组小鼠搔鼻症状相对于抗体对照组明显减轻(P<0.05),与PBS 组比较,OVA 组小鼠鼻黏膜炎症细胞浸润明显(P<0.01),鼻腔灌洗液中嗜酸性粒细胞数明显升高(P<0.05);抗IL-23p19 抗体治疗后,小鼠鼻黏膜炎症细胞浸润显著降低(P<0.05),鼻腔灌洗液中嗜酸性粒细胞数明显降低(P<0.05);抗IL-23p19 抗体治疗后,IL-4 及IL-17A 含量较IgG 抗体对照组降低(P<0.05),IFN-β含量不变(P>0.05)。抗IL-23p19 抗体治疗后,FOXP3 含量较IgG 抗体对照组增高(P<0.05)。结论:抗IL-23p19 抗体可有效治疗小鼠变应性鼻炎,其机制可能是抑制Th17 细胞的增殖并且促进调节性T 细胞的功能。     

Clara细胞10 kD蛋白通过调控T细胞反应治疗小鼠变应性鼻炎研究北大核心CSCD

目的:探讨Clara细胞10 kD蛋白(CC10)对变应性鼻炎(AR)小鼠模型T细胞反应的作用。方法:卵清蛋白(OVA)免疫小鼠,建立AR模型,探讨CC10对AR的影响。最后1次鼻腔激发后评估小鼠鼻腔症状。收集鼻组织和鼻腔灌洗液(NLF),测定AR小鼠嗜酸性粒细胞、杯状细胞数及IL-5、IL-17、IL-10、TGF-β1、FOXP3水平。结果:激发期间给予CC10可显著减少AR小鼠搔鼻次数、嗜酸性粒细胞和杯状细胞数,降低IL-5、IL-17水平(P<0.05),但可增加IL-10、TGF-β1和FOXP3表达(P<0.05)。结论:CC10可通过调控T细胞反应减轻AR小鼠鼻腔炎症。     

变应性鼻炎和哮喘患者血清IL-5、IL-15及IL-18的水平研究

目的探讨IL-5、IL-15和IL-18在变应性鼻炎、支气管哮喘、变应性鼻炎合并哮喘疾病中的作用。方法采用双抗体夹心ELISA测定法对33例支气管哮喘患者、35例变应性鼻炎患者、35例变应性鼻炎合并哮喘的患者及35例正常健康查体者血清中IL-5、IL-15和IL-18的水平进行检测。结果支气管哮喘、变应性鼻炎、变应性鼻炎合并哮喘的患者血清中IL-5、IL-15和IL-18水平较正常对照组升高（P〈0．01）,IL-5、IL-15,IL-18水平在变应性鼻炎合并哮喘组均高于鼻炎组与和哮喘组;鼻炎组IL-5水平高于哮喘组（P=0．003）,哮喘组IL-18水平高于鼻炎组（P=0．001）。结论IL-5、IL-15和IL-18参与了过敏性鼻炎和哮喘的发病过程;变应性鼻炎合并哮喘的炎症程度较高;哮喘和鼻炎因发病部位不同炎症反应也有不同。     

TNF-α、IL-10在变应性鼻炎中的作用研究

目的 通过检测变应性鼻炎(AR)患者血清TNF-α、IL-10在治疗前后的表达变化,探讨二者在变应性鼻炎中的作用.方法 收集33例正常健康对照组以及48例变应性鼻炎患者行脱敏治疗前后的血清标本,应用双抗体夹心ELISA方法测定血清中TNF-α、IL-10的表达水平,SPSS12.0软件进行统 计学分析.结果 TNF-α在AR患者血清中高表达,与对照组相比差异具有统计学意义(P =0.0028),脱敏治疗后其表达下降,治疗前后相比有统计学差异(P =0.0032);IL-10在患者血清中表达低于对照组,差异具有统计学意义(P=0.018),脱敏治疗后其表达上升,与治疗前相比差异有统计学意义(P=0.024);TNF-α、IL-10在AR患者中的表达呈负相关(r=-0.413,P＜0.05).结论 TNF-α和IL-10在变应性鼻炎发病过程中可能起到重要作用.     

Th9细胞亚群在变应性鼻炎中的研究进展

CD4+ T辅助细胞包括T辅助细胞1型(Th1)、Th2、Th17和Treg等。Th2细胞在变应性疾病中的重要免疫作用一直得到了较广泛认可。IL-9也一直被视为一种Th2型细胞因子,在变态反应中贡献突出。最近的研究发现了一种独特的产IL-9的CD4+ T辅助细胞,这种新型亚群被命名为Th9细胞亚群,其在变应性鼻炎中的作用研究还很少,本文将就Th9细胞以及其产生的特异性细胞因子IL-9在变应性鼻炎中的研究进展做以阐述。     

新型免疫抑制因子IL-35研究新进展

IL-35是一种由调节性T细胞(Tr)分泌具有免疫负调作用的新型细胞因子.IL-35通过抑制IL-17等效应分子发挥免疫调节作用,研究表明,Tr、IL-35和Th17参与了自身免疫性疾病,炎症与肿瘤的免疫调节,因此IL-35的上游激活以及下游效应反应机制值得进一步研究探讨.     

鼻炎清颗粒治疗变应性鼻炎的免疫机制研究

目的:观察鼻炎清颗粒治疗大鼠变应性鼻炎(AR)后,细胞因子、血清特异性IgE和嗜酸粒细胞阳离子蛋白(ECP)的水平,了解该药治疗AR的部分免疫学机制.方法:用卵清蛋白(OVA)、氢氧化铝、百白破疫苗联合致敏大鼠建立变应性鼻炎动物模型,鼻炎清颗粒灌胃给药2周后,观察鼻黏膜组织学变化,ELISA法检测血清细胞因子IL-4、 IFN-γ、 IgE 和ECP的水平.结果:光镜观察发现,模型组鼻黏膜上皮细胞脱落、水肿、血管扩张、腺体增生,固有层内可见大量嗜酸性粒细胞、肥大细胞浸润,治疗组大剂量和中剂量组及阴性对照组则无上述改变.治疗组大、中剂量组血清IL-4水平分别为(10.30±4.41) ng/L 和(12.42±6.55) ng/L,明显低于模型组(17.62±6.10) ng/L,有统计学差异(P＜0.01或P＜0.05);而IFN-γ水平分别为(34.19±6.16) ng/L和(27.92±6.47) ng/L,明显高于模型组(19.33±5.63) ng/L(P＜0.01);3种剂量组的血清IgE水平分别为(26.46±6.12) μg/L、 (49.11±4.48) μg/L和(70.68±7.59) μg/L,与阳性模型组(81.03±7.54) μg/L,相比较有统计学差异(P＜0.01或P＜0.05);血清ECP水平分别为(1.48±0.25) μg/L,(2.30±0.56) μg/L和(3.05±1.27) μg/L,与阳性模型组(4.23±1.20) μg/L比较,大、中剂量组有统计学意义(P＜0.01或P＜0.05),小剂量组无统计学意义.结论:鼻炎清颗粒通过调节Th1和Th2细胞因子的表达,纠正失衡的Th1/Th2的细胞因子网络,降低血清特异性IgE和ECP水平和抑制炎症细胞在鼻黏膜的聚集,防止其脱颗粒,对变应性鼻炎产生治疗作用.     

Mechanism of IL-10-induced T cell inactivation in allergic inflammation and normal response to allergens

BACKGROUND: Induction of specific unresponsiveness (tolerance/anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy (SIT) with whole allergen or antigenic T cell peptides. METHODS: Antigen-specific T cell responses and molecular mechanisms of T cell inactivation were investigated during conventional SIT, T cell epitope peptide immunotherapy and natural exposure to bee venom in allergic and hyperimmune individuals. RESULTS: T cell unresponsiveness, initiated by autocrine action of IL-10, is characterized by suppressed proliferative and cytokine responses. The unresponsive T cells can be reactivated by different cytokines that may mimic the microenvironmental cytokine influence. IL-10 initiates peripheral tolerance by blocking the CD28 costimulatory signal in T cells. Coprecipitation experiments reveal that upon stimulation CD28 and IL-10 receptor are physically associated in T cells. Accordingly, IL-10 binding to its receptor inhibits CD28 tyrosine phosphorylation, the initial step of the CD28 signaling pathway. This leads to inhibition of phosphatidylinositol 3-kinase p85 binding to CD28. IL-10 only affects T cells that receive a stimulation with low numbers of triggered T cell receptors and that require costimulatory signals by CD28. CONCLUSION: These data demonstrate the pivotal role of autocrine IL-10 and the interaction of its receptor with CD28 in the induction of T cell tolerance as an immunoregulatory mechanism controlling antigen-specific T cell responses.     

IL-32 up-regulation is associated with inflammatory cytokine production in allergic rhinitis

IL-32 is a described pro-inflammatory cytokine produced by T lymphocytes, natural killer cells, monocytes, and epithelial cells. However, the specific mechanism of IL-32 on allergic rhinitis (AR) has not been elucidated. Here, we report a significant increase of IL-32 protein and mRNA in the nasal mucosa of AR patients. In addition, in nasal mucosa tissue from AR patients, the level of IL-32 production correlated with inflammation, IL-1β, IL-18, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In an AR animal model, IL-32 significantly increased IgE and inflammatory cytokine levels. IL-32 expression was induced by recombinant human GM-CSF via activation of caspase-1 in eosinophils. In addition, depletion of IL-32 prevents the production of inflammatory cytokines in eosinophils. In conclusion, IL-32 is an important cytokine involved in the inflammation of AR. The regulation of IL-32 expression may form the basis of a new strategy for the treatment of AR.     

IL-13 is essential to the late-phase response in allergic rhinitis

BACKGROUND: The pathophysiology of the early- and late-phase nasal response to allergen challenge is not completely defined. Recent technical advances enable direct monitoring of these responses in mice. OBJECTIVE: IL-13 is detected in the nasal membranes of both human beings and mice with allergic rhinitis, but its role in disease pathogenesis is unclear. We measured early and late nasal allergic responses after treatment with soluble IL-13Ralpha2-IgG fusion protein (sIL-13Ralpha2-Fc), and in IL-13-deficient mice (IL-13(-/-)). METHODS: IL-13(-/-) mice (BALB/c background) and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged intranasally with ovalbumin without sedation. The sIL-13Ralpha2-Fc or control human IgG was administered by intraperitoneal (i.p.) injection 24 hours and 1 hour before each ovalbumin challenge. Early nasal responses after the 4th ovalbumin challenge and late nasal responses 24 hours after the 6th ovalbumin challenge were assessed. RESULTS: Sensitized/challenged wild-type mice treated with sIL-13Ralpha2-Fc or IL-13(-/-) mice demonstrated significantly reduced late nasal responses in face of persistent nasal tissue eosinophilia; the early nasal response was little affected by targeting IL-13. Goblet cell hyperplasia was not detected in nasal membranes. CONCLUSION: The data indicate that IL-13 is a major contributor to the development of a late nasal response with little influence on the early response, and without affecting nasal eosinophilic inflammation. Inhibition of IL-13 may have an important therapeutic application in preventing the persistent nasal blockage in allergic rhinitis. CLINICAL IMPLICATIONS: Current therapies for allergic rhinitis may not take into account the important differences in the pathophysiology of the early and late responses and the important role of IL-13 in sustaining chronic nasal congestion and obstruction.     

Up-regulation of IL-18 in allergic rhinitis

BACKGROUND: This paper reports a study on the concentrations of the pro-inflammatory cytokines IL-18 and IL-1beta in nasal secretions of allergic rhinitis patients in relation to ECP and nasal symptoms. METHODS: We measured IL-18 and IL-1beta concentrations using ELISA, and eosinophilic cationic protein (ECP) using the CAP system, in nasal secretions of 15 seasonal allergic rhinitis (SAR) patients at six visits throughout the pollen season. Pollen exposure, nasal and ocular symptoms were monitored daily. Furthermore, we measured IL-18, IL-1beta and ECP concentrations in nasal secretions of 19 controls and 20 symptomatic persistent allergic rhinitis (PAR) patients with house dust mite allergy. RESULTS: In SAR, the increase of IL-18, IL-1beta and ECP paralleled the pollen flight with a time delay. IL-18 and IL-1beta significantly increased during the pollen season compared to baseline, and differently from ECP, remained elevated until 4 weeks after the season. In PAR, the concentrations of IL-18 and ECP, but not IL-1beta, were significantly higher compared to controls, with IL-18 concentrations also being significantly higher than in SAR. CONCLUSION: This is the first study to demonstrate the up-regulation of IL-18 in nasal secretions in allergic rhinitis. The persistence of elevated IL-18 concentrations until after the season and the high concentrations in PAR compared to SAR suggests its role in persistent allergic inflammation.     

T cell responses in allergic rhinitis, asthma and atopic dermatitis

Although clinical responses to allergens have been shown to primarily involve IgE antibodies, there is often no clear correlation between the amount of allergen-specific IgE present in the serum and the nature and severity of allergic symptoms. This observation raises the question of the possible role of non-IgE mediated types of immune responses in this reaction. It is not known to what extent components of T cell-mediated immunity are involved in IgE-mediated reactions but several observations suggest an association between atopic disease and alterations in cellular immune function. These include the frequent association of high serum IgE levels with: (i) several of the primary and acquired immunodeficiencies characterized by partial T cell deficiency; (ii) the defective cell-mediated immunity and resultant recurrent infections seen in the hyper-IgE syndrome; and (iii) the sudden rise in serum IgE levels associated with reduced numbers of suppressor T cells in bone marrow transplant recipients during the acute graft vs host disease. In this review, we will examine the recent evidence suggesting that the T lymphocyte may play a primary role in the pathogenesis of atopic disorders.     

Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders

Homeostasis in the gastrointestinal tract relies on a sensitive equilibrium between permissive and protective functions. This is closely reflected in the regulation of the intestinal immune system and especially T cells in the gut. This balance, however, is susceptible to disturbances as demonstrated by pathological conditions like food allergy, celiac disease, or inflammatory bowel disease. In these allergic and chronic inflammatory bowel disorders, luminal antigens get access to the lamina propria where they trigger a dysregulated immune response with crucial involvement of different T cell subsets. We will begin this review with some comprehensive remarks on current concepts on the pathogenesis of these diseases before taking a closer look at the life cycle of intestinal T cells consisting of priming, homing, differentiation and proliferation and apoptosis respectively. Subsequently we will discuss the specific implication of distinct T cell subsets in allergic and chronic inflammatory conditions of the gastrointestinal tract in detail and comment on current and future approaches to targeted therapy in this context.     

脂肪间充质干细胞可调节变应性鼻炎T细胞的免疫状态

BACKGROUND: Adipose-derived mesenchymal stem cells are a kind of pluripotent stem cells that have the potential of self-renewal and proliferation, and have low immunogenicity and immunomodulatory role. OBJECTIVE: To study the effects of adipose-derived mesenchymal stem cells on T cell immune status of allergic rhinitis mouse models. METHODS: Sixty mice were randomly assigned into six groups (sensitized/challenged/treatment): experimental group 1 was given ovalbumin/ovalbumin/high-dose adipose-derived mesenchymal stem cells, experimental group 2 given ovalbumin/ovalbumin/low-dose adipose-derived mesenchymal stem cells, experimental group 3 given ovalbumin/ovalbumin/PBS, experimental group 4 given ovalbumin/ovalbumin/0, and experimental group 5 given PBS/PBS/0, and normal control group given no treatment. In the former five groups, intraperitoneal injection of 200 μL ovalbumin sensitizing solution or PBS was conducted for basic sensitization at days 0, 7, 14; 20 μL ovalbumin challenging solution or PBS was given for challenging at days 15-19. In the former three groups, 0.1 mL of high-dose, low-dose adipose-derived mesenchymal stem cells or PBS was given via the tail vein, respectively, at days 20-22 after sensitization and challenge. At 48 hours after final treatment, ELISA was used to detect serum levels of interleukin-4, interleukin-6, interleukin-10 and interferon-γ, and fluorogenic quantitative PCR used to detect the mRNA expressions of these cytokines in the spleen. Migration of fluorescent-labeled adipose-derived mesenchymal stem cells in the nasal mucosa was observed under fluorescence microscope, and pathological changes of the nasal mucosa were observed through hematoxylin-eosin staining. RESULTS AND CONCLUSION: Compared with the experimental group 4, the levels of interleukin-4 and interleukin-6 in the serum and spleen were significantly lower in the experimental group 1 (P < 0.05), and the levels of interluekin-10 and interferon-γ levels were significantly increased (P <0.05); while in the experimental group, the levels of interleukin-6 were reduced significantly (P < 0.05), the levels of interleukin-10 was increased significantly (P < 0.05), but no changes were found in the levels of interleukin-4 and interferon-γ (P > 0.05). Fluorescent-labeled adipose-derived mesenchymal stem cells could migrate into the nasal mucosa, and the number of migrated cells was notably higher in the experimental group 1 than experimental group 2. Eosinophil infiltration in the nasal mucosa was remarkably alleviated in the experimental groups 1 and 2. These findings suggest that adipose-derived mesenchymal stem cells play a non-specific immunomodulatory effect dose-dependently by regulating Th1/Th2 immune imbalances and deficiencies of Treg cells.