支气管哮喘的细胞因子治疗进展

哮喘是一种慢性气道炎症性疾病,它的发生和发展与多种细胞因子密切相关.目前哮喘还没有有效的预防和治愈方法,细胞因子抑制剂已经作为潜在的治疗手段而被广泛研究.其中IL-4、IL-5、TNF-α抑制剂的临床研究已经取得了突破性的进展.IL-13和IL-9的临床试验正在研究中.对哮喘动物模型的大量研究发现了胸腺基质淋巴细胞生成素(TSLP),IL-17等新的相关细胞因子,这为哮喘细胞因子治疗提供了新的思路.而多种细胞因子抑制剂的联合使用也为治愈哮喘提供了可能.同时,哮喘个体化医疗的研究为逆转哮喘提供了有力保障.     

Bone marrow-derived mononuclear cells vs. mesenchymal stromal cells in experimental allergic asthma

We compared the effects of bone marrow-derived mononuclear cells (BMMCs) and mesenchymal stromal cells (MSCs) on airway inflammation and remodeling and lung mechanics in experimental allergic asthma. C57BL/6 mice were sensitized and challenged with ovalbumin (OVA group). A control group received saline using the same protocol. Twenty-four hours after the last challenge, groups were further randomized into subgroups to receive saline, BMMCs (2 × 10⁶) or MSCs (1 × 10⁵) intratracheally. BMMC and MSC administration decreased cell infiltration, bronchoconstriction index, alveolar collapse, collagen fiber content in the alveolar septa, and interleukin (IL)-4, IL-13, transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) levels compared to OVA-SAL. Lung function, alveolar collapse, collagen fiber deposition in alveolar septa, and levels of TGF-β and VEGF improved more after BMMC than MSC therapy. In conclusion, intratracheal BMMC and MSC administration effectively modulated inflammation and fibrogenesis in an experimental model of asthma, but BMMCs was associated with greater benefit in terms of reducing levels of fibrogenesis-related growth factors.     

甲基强的松龙对哮喘患儿PBMC分泌TH源性细胞因子的影响作用研究

目的　了解皮质激素对哮喘患者TH1/TH2功能失衡的调节作用 ,探讨其治疗哮喘的机制。方法　将临床 30例哮喘患儿随机分为甲基强的松龙 (MP)治疗组和对照组 ,用ELISA法测外周血单个核细胞 (PBMC)细胞因子及血清IgE水平 ,用逆转录 聚合酶链反应 (RT PCR)测定细胞因子mRNA表达。结果　MP组临床症状和体征消失时间明显缩短 ;MP对T辅助细胞 (TH)源性细胞因子和血清IgE均有抑制作用 ,但对IL 4、IL 10的抑制作用强于对IFN γ、IL 2的抑制作用 ;MP抑制IL 4mRNA表达程度强于对IFN γ表达抑制。结论　皮质激素可能部分通过调节哮喘患者TH 亚群分泌细胞因子而在治疗中起作用。     

Chitinases and chitinase-like proteins in asthma

Despite the lack of endogenous chitin synthesis, mammalian genomes encode two enzymatically active true chitinases (chitotriosidase and acidic mammalian chitinase) and a variable number of chitinase-like proteins (CLPs) that have no enzyme activity but bind chitin. Chitinases and CLPs are prominent components of type-2 immune response-mediated respiratory diseases. However, despite extensive research into their role in allergic airway disease, there is still no agreement on whether they are mere biomarkers of disease or actual disease drivers. Functions ascribed to chitinases and CLPs include, but are not limited to host defense against chitin-containing pathogens, directly promoting inflammation, and modulating tissue remodeling and fibrosis. Here, we discuss in detail the chitin-dependent and -independent roles of chitinases and CLPs in the context of allergic airway disease, and recent advances and emerging concepts in the field that might identify opportunities for new therapies.     

Current control and future risk in asthma management

Despite international and national guidelines, poor asthma control remains an issue. Asthma exacerbations are costly to both the individual, and the healthcare provider. Improvements in our understanding of the therapeutic benefit of asthma therapies suggest that, in general, while long-acting bronchodilator therapy improves asthma symptoms, the anti-inflammatory activity of inhaled corticosteroids reduces acute asthma exacerbations. Studies have explored factors which could be predictive of exacerbations. A history of previous exacerbations, poor asthma control, poor inhaler technique, a history of lower respiratory tract infections, poor adherence to medication, the presence of allergic rhinitis, gastro-oesophageal reflux disease, psychological dysfunction, smoking and obesity have all been implicated as having a predictive role in the future risk of asthma exacerbation. Here we review the current literature and discuss this in the context of primary care management of asthma.     

Toll样受体7作为新靶点在过敏性及自身免疫性疾病中的研究进展

Toll样受体(Toll-like receptors,TLRs)属于模式识别受体(pattern recognition receptors,PRRs)家族,通过迅速识别入侵微生物病原相关分子模式(pathogen-associated molecular patterns,PAMP)激活下游信号传导途径,引发机体的免疫反应,是连接固有免疫与适应性免疫的桥梁.目前在人类发现10种不同TLRs,分别命名为TLR1 ～TLR10.近年的研究显示,TLR7与过敏性疾病、自身免疫性疾病—过敏性哮喘、系统性红斑狼疮(systemic lupus erythematosus,SLE)等有密切的联系.TLR7的激活状态影响上述疾病的发生、发展和预后.这些证据预示TLR7可能作为潜在靶点为哮喘和SLE的治疗提供新的方向.     

黄芪在树突状细胞水平对哮喘TH 1/TH 2平衡的调节作用

目的 探讨黄芪在树突状细胞(DC)水平对过敏性哮喘TH/TH2平衡的调节作用.方法 用rhGM-CSF和rhIL-4诱导培养外周血来源的DC并予鉴定,ELISA法检测其分泌的细胞因子IL-12、IL-10以及与自身T细胞反应后,RT-PCR检测T-bet和GATA-3 mRNA含量,流式细胞术检测T细胞分泌的胞内细胞因子IL-4和IFN-γ水平.结果 哮喘患儿外周血DC分泌IL-10高于对照组(P＜0.05);黄芪干预后DC分泌IL-10降低,与哮喘组比较差异有统计学意义(P＜0.05).哮喘患儿外周血DC分泌IL-12低于对照组(P＜0.05);黄芪干预后DC分泌IL-12增加,但与哮喘组比较差异无统计学意义.混合培养第7天哮喘组T细胞内IL-4水平显著高于正常对照组(P＜0.01);而IFN-γ水平则显著低于正常对照组(P＜0.05);哮喘组IL-4/IFN-γ比值高于正常对照组(P＜0.01).黄芪干预后T细胞内IL-4水平与哮喘组比较差异无统计学意义,而IFN-γ水平增加,与哮喘组比较差异有统计学意义(P＜0.05),IL-4/IFN-γ比值降低,与哮喘组比较差异有统计学意义(P＜0.01).哮喘组T-bet mRNA的表达强度明显低于正常对照组(P＜0.01);而哮喘组GATA-3 mRNA的表达强度则明显高于正常对照组(P＜0.05);哮喘组GATA-3/T-bet比值高于正常对照组(P＜0.05).黄芪干预后T细胞GATA-3 mRNA的表达强度与哮喘组比较差异无统计学意义,而T-bet mRNA水平增加,与哮喘组比较差异有统计学意义(P＜0.05),GATA-3/T-bet比值降低,与哮喘组比较差异有统计学意义(P＜0.01).结论 哮喘患儿DC功能缺陷,产生IL-12减少、IL-10增加导致TH2优势分化,从而使TH1/TH2平衡向TH2倾斜,合成IFN-γ减少,进而造成气道慢性炎症、气道高反应性而致哮喘发作.黄芪对DC的调节主要通过降低IL-10的分泌水平,从而降低其抑制TH0细胞向TH 1分化的功能,即间接抑制了TH0细胞向TH2的分化.     

Future forms of immunotherapy and immunomodulators in allergic disease

Future forms of immunotherapy, particularly toll-like receptor agonists, have shown promising results in animal models of allergic disease although most have failed to translate into successful human clinical trials. These results have helped to elucidate the pleotropic roles of cytokines as well as the diverse phenotypes of allergic diseases, particularly asthma. The goals of these therapies are to improve patient symptoms and quality of life, to prevent and favorably alter disease course, and to maintain a good risk/benefit ratio along with a cost-effective profile.     

维吾尔药大苞荆芥总多糖对哮喘大鼠细胞因子的影响

目的观察维吾尔药大苞荆芥总多糖对大鼠哮喘模型细胞因子的影响,探讨其治疗哮喘的作用机制。方法将大鼠随机分为正常对照组、哮喘组、地塞米松组、大苞荆芥总多糖低、高剂量组;除正常对照组外,各组大鼠用卵白蛋白致敏和激发,建立哮喘模型。用ELISA法检测血清IL-4、IL-6、IL-17和IFN-γ水平,HE染色观察肺组织病理改变。结果与哮喘组相比,各治疗组血清IL-4、IL-6、IL-17水平明显下降(P<0.01),IFN-γ水平明显升高(P<0.01);总多糖低剂量组各指标与地塞米松组有统计学差异(P<0.05),高剂量组与之无明显差异;与总多糖低剂量组相比,高剂量组血清IL-4、IL-6、IL-17水平明显下降、IFN-γ水平明显上升(P<0.05);各组大鼠血清IL-4与IFN-γ水平呈负相关关系(r=-0.450,P<0.05),IL-4与IL-6、IL-4与IL-17,IL-6与IL-17均呈正相关关系(r分别为0.796、0.462和0.638,P<0.05)。结论大苞荆芥总多糖可抑制炎性细胞因子IL-4、IL-6、IL-17的释放,这或许是治疗哮喘的一条有效途径。     

Comparison of allergic indices in monosensitized and polysensitized patients with childhood asthma

Monosensitization differs both immunologically and clinically from polysensitization, and specific immunotherapy is more effective in patients sensitized only to a single pollen than in multiple-pollen sensitized patients. To further examine the differences between monosensitized and polysensitized allergies, allergic indices were examined in 68 monosensitized and 62 polysensitized patients with childhood asthma. Measurements included symptom scores, eosinophil counts, skin prick tests, serum total and specific IgE levels, and IL-10 levels, and were used to compare allergic indices between the two groups. Patients were followed for 18 months following immunotherapy to examine the effectiveness of the treatment. Symptom scores and total IgE levels were significantly higher in the polysensitized group than those in the monosensitized group (p<0.05). The levels of skin test response decreased significantly in both groups following immunotherapy. In the monosensitized group, symptom scores and specific IgE levels were significantly reduced after immunotherapy (p<0.05). In the polysensitized group, symptom scores were reduced after immunotherapy (p<0.05), but the degree of reduction was less than that of the monosensitized group (p<0.05). Moreover, in the polysensitized group, specific IgE levels after immunotherapy did not differ from that before immunotherapy. Serum IL-10 levels were not significantly increased after immunotherapy in either group. In conclusion, polysensitized patients tend to show higher allergic indices and immunotherapy might be less effective for these patients.     

Nasal nitric oxide in upper airways in children with asthma and allergic rhinitis

PurposeThe aim of this study is to compare levels of nasal nitric oxide (nNO) in pediatric patients with respiratory diseases.Materials and methodsnNO was measured by an electrochemical analyzer in 179 patients aged 7–15 with asthma, allergic rhinitis or with asthma and allergic rhinitis and in healthy children recruited from a local allergology clinic. Correlations between nNO levels and patient clinical parameters were assessed.ResultsnNO was significantly higher in patients with allergic rhinitis (2316.3 ± 442.33 ppb, p < 0.001) as well as with asthma and allergic rhinitis (2399.9 ± 446.73 ppb, p < 0.001) compared to asthmatic and healthy children (1066.4 ± 416.75; 836.2 ± 333.47 ppb, respectively). A receiver operating characteristic curve analysis revealed that a cut-off value of 1545 ppb nNO and 1459 ppb nNO has sensitivity of 100% and specificity of 100% in distinguishing allergic rhinitis and combined asthma and allergic rhinitis from healthy subjects. A positive correlation between nNO and age and height was determined only in groups of healthy controls. We found no association between nNO level and clinical parameters including percent of eosinophils and total IgE.ConclusionLevels of nNO are currently measured by different analyzers and with different methods, so assessment of nNO is in need of standardization improvement to become a more reliable tool. However, because it is cheap, painless and fast, it may be helpful in combination with recognition of clinical symptoms and typical diagnostic methods, especially in estimation of inflammation.     

HLA and asthma phenotypes/endotypes: A review

Asthma is a complex chronic inflammatory disease of the airways caused by the interaction of genetic susceptibility with environmental influences. Genome-wide association studies (GWAS) represent the most powerful approach for asthma, that have identified several genes (e.g., IL18R1, IL33, SMAD3, ORMDL3, HLA-DQ and IL2RB loci). HLA super-locus is a genomic region in the chromosomal position 6p21. Since no gene can be considered as an asthma gene, able to reflect the complex etiology and the heterogeneity of the disease the terms ‘phenotype’ and more recently ‘endotype’ have been used. This review, according to literature availability, focuses on the relationship between human leukocyte antigens (HLA) region specifically the HLA class II genes and different asthma phenotypes/endotypes, such as allergic asthma/Th2 associated, occupational and aspirin-sensitive asthma. The most common HLA haplotypes in the different asthma phenotypes are HLA-DRB1in allergic asthma, HLA-DQB1in occupational asthma and HLA-DPB1 in aspirin-sensitive asthma. However, it is difficult to study the role of class II genes in vivo because of the heterogeneity of human population, the complexity of MHC, and the strong linkage disequilibrium among different class II genes. Despite the variation and the inconsistency of the HLA haplotypes and alleles in different types of asthma, the association between HLA class II genes and asthma has been demonstrated in the majority of studies.     

The potential of anti‐infectives and immunomodulators as therapies for asthma and asthma exacerbations

Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning >20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti‐infectives in Asthma was initiated to investigate the potential of anti‐infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti‐infectives and both microbe‐ and host‐based immunomodulators and their feasibility for use in asthma.     

外周血T细胞亚群及细胞因子对外源性哮喘IgE生成的作用

对３０例哮喘患者及３０例健康成年人的外周血，采用单克隆抗体（ＭｃＡｂ）间接免疫荧光法测定Ｔ细胞亚群；ＥＬＩＳＡ双抗体夹心法测定ＩｇＥ、ＩＬ－４；ＦＩ２细胞株，生物学方法测定ＩＬ－２；ＩＬ－６依赖细胞株７ＴＤ１，掺入法测定ＩＬ－６；用抗人ＣＤ２３的ＭｃＡｂ测定ＣＤ２３。为研究Ｔ细胞、细胞因子对哮喘ＩｇＥ生成调节机理及细胞因子在哮喘发病过程中的作用。结果显示：发作期ＩｇＥ、ＩＬ－２、ＩＬ－４、ＣＤ２３、ＣＤ８~＋、ＣＤ４／ＣＤ８~＋比值较对照组及缓解期有显著性差异（Ｐ＜０．０１）。缓解期ＩｇＥ与对照组之间无显著性差异（Ｐ＞０．０５）；ＣＤ８＋、ＣＤ４／ＣＤ８比值，ＣＤ２３与对照组之间有显著性差异（Ｐ＜０．０１）。ＣＤ２３、ＣＤ４、ＩＬ－６三组间无显著性差异（Ｐ＞０．０５）。结果表明，ＩｇＥ合成增加是哮喘发作的关键，Ｔ细胞对日细胞合成ＩｇＥ的调节是通过细胞因子实现的，细胞因子又参与气道炎症过程。     

Korean ginseng-induced occupational asthma and determination of IgE binding components

A number of case reports on occupational asthma caused by herbal medicines have been issued, for example, on Sanyak, Chunkung, Banha, and Brazilian ginseng. Recently, cases of occupational asthma induced by Sanyak and Korean ginseng have been reported, but the pathogenic mechanisms involved are unknown. This study was carried out to evaluate the immunologic mechanism underlying Korean ginseng-induced occupational asthma. A patient engaged in Korean ginseng wholesale was referred for recurrent dyspnea, wheezing, and nasal symptoms, which were aggravated at work. Allergen bronchial provocation testing to Korean ginseng extract showed a typical immediate response, and skin prick testing to Korean ginseng extract also showed a strong positive response. Moreover, serum-specific IgE levels to Korean ginseng extract were significantly higher than in controls. Enzyme-linked immunosorbent assay (ELISA) inhibition tests showed a dose-dependent inhibition by Korean ginseng, but not by Dermatophagoides farinae, wheat flour, or Chinese balloon flower. Sodium dodecylsulfate-poly-acrylamide gel electrophoresis (SDS-PAGE) and immunoblotting revealed four specific Immunoglobulin E (IgE) binding components at 26, 30, 47, and 60 kDa, which were not bound by control sera. These results strongly suggest that occupation asthma induced by Korean ginseng is induced via an IgE-mediated mechanism.     

新鲜羊膜致I型超敏反应的变应原性研究

研究新鲜人羊膜的变应原性及其致敏后发生I型超敏反应的可能性。建立豚鼠全身主动过敏实验模型。分新鲜羊膜组、新鲜蛋清组(阳性对照)和PBS液组(阴性对照),每组10只豚鼠。观察豚鼠在致敏期和激发后的反应,采用化学荧光法检测外周血组胺含量,血液流变分析系统检测4项血液流变学指标(全血高切变率黏度、全血低切变率黏度、血浆黏度、红细胞聚集指数)。致敏期间各组豚鼠的体重变化无明显差别(P>0.05);激发后羊膜组豚鼠与阴性组表现一致,无异常反应;羊膜组外周血组胺含量及4项血液流变学指标均与阴性对照无明显差别(P>0.05),与阳性对照有显著性差异(P<0.01)。经规范化无菌处理后的新鲜羊膜,一般不具有变应原性,不会引起I型超敏反应。     

Association of CD14 promoter polymorphisms and soluble CD14 levels in mite allergen sensitization of children in Taiwan

CD14 is responsible for environmental lipopolysaccharide recognition and is a positional candidate gene for allergy. We hypothesized that genetic polymorphisms in the promoter region of the CD14 gene may be associated with Dermatophagoides pteronysinnus (Der p) allergen sensitization in children. Three single nucleotide polymorphisms (SNPs) of the CD14 promoter region, C(–159)T, A(–1,145)G, and G(–1,359)T were genotyped, and analyzed in 240 randomized case–control school-age children in Taiwan. Serum concentrations of IgE and soluble CD14 (sCD14) were also assayed. We found a significant inverse correlation of sCD14 and total serum IgE levels in our study population. Moreover, sCD14 binds Der p allergen in vitro in a dose-dependent manner. The distribution of three SNPs genotypes was similar in asthmatic children and the control group. However, there was a significant difference in the distribution of genotype CD14 G(–1,359)T, but not C(–159)T, between mite-sensitive and non-sensitive children. Haplotype analysis showed strong linkage disequilibrium among these three SNPs in the CD14 promoter region. Carriers of the CD14–159C/–1,145A/–1,359T haplotype had the highest IgE and lowest sCD14 levels as compared to other haplotypes. Our results support the hypothesis that CD14 gene variants may play an important role in influencing allergen sensitization of children in Taiwan.