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WAO News & Notes - October 2007
Volume 4, Issue 10

Medical Journal Reviews
医学期刊回顾†† 200710月(第10期)

Medical Journal Reviews


Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief, and Guest Reviewer Gary Hellermann, PhD, reviewed premier medical journal articles for practicing allergists.

Richard F. Lockey教授,医学博士,WAO网站主编;Gary Hellermann, 博士,为从业的变态反应科医生回顾了主要医学期刊的一些重要文章

1. L-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities.

Using a mouse model of bacterial sepsis, the authors found that IL-15 deficiency improves survival. IL-15 enhances the immune response by activating T cells, thymocytes, B cells and natural killer cells. In this study, IL-15 inhibits transcription of mast cell protease-2 (chymase), an enzyme that breaks down a cellular protein to yield neutrophil-activating protein-2 (NAP-2), which recruits neutrophils to the infection site. The protease-2 activity is regulated by IL-15, and deletion of IL-15 in mice results in more rapid bacterial killing and improves survival in this experimental sepsis model. Editorís comment: Inhibiting IL-15 production within mast cells may improve sepsis survival in humans. Orinska Z et al. Nature Med 2007; 13:927-934. (Editorial: Ward PA, 13:903)



作者们用细菌败血症的小鼠模型发现,白细胞介素-15缺乏可提高生存率。白细胞介素-15 可通过活化T淋巴细胞、胸腺细胞、B细胞和自然杀伤细胞而增强免疫反应。在这项研究中,白细胞介素-15抑制肥大细胞蛋白酶-2 (糜蛋白酶)的转录,该酶可分解细胞蛋白质生成中性粒细胞活化蛋白2NAP- 2),而NAP-2可趋化中性粒细胞到感染部位。白细胞介素-15可调节肥大细胞蛋白酶-2的活性。在这个实验性败血症小鼠模型,白细胞介素-15缺乏可更迅速杀死细菌并改善生存。编者按:抑制肥大细胞产生白细胞介素-15可改善人类败血症生存。Orinska Z et al. Nature Med2007; 13:927-934. (Editorial: Ward PA, 13:903)


2. Allergen immunotherapy: a practice parameter second update.

The September supplement to JACI is the second allergen immunotherapy practice parameter docu- ment. It includes 352 references and thoroughly covers the science of various forms of allergen immunotherapy. Following the introduction, subjects such as mechanisms, available allergen ex- tracts, efficacy, safety, patient selection, schedules and doses, and other aspects of treatment are thoroughly covered. Each section starts out with a summary statement followed by its scientific rationale. Editorís comment: This practice parameter is a must read for every allergist who prescribes allergen immunotherapy. Cox et al. JACI 2007; 120:S25.



JACI杂志9月增刊是过敏原特异性免疫疗法的第二个循证指南文件。它包括352份参考文献,全面涵盖了不同种类过敏原特异性免疫疗法的科学资料。在序言之后,免疫疗法的机制、现有的过敏原提取物、疗效、安全性、患者的选择、治疗方案和剂量及治疗的其他方面等各个方面都全面涵盖。每一节都以一个总结性的陈述开始,然后展开科学论述。编者按:每个开展过敏原特异性免疫治疗的变态反应医生都应该阅读该文件。Cox et al. JACI 2007; 120:S25.


3. Anti-inflammatory effects of high-dose inhaled fluticasone (F) versus oral prednisone (P) in moderate asthma exacerbations.

A randomized clinical trial. From a group of 45 asthmatic patients treated for moderate asthma in the Emergency Room, 19 received F plus P placebo while 20 received P plus F placebo. Smokers and those with serious chronic illness or treated with oral or i.v. corticosteroids within four weeks before the study were excluded. F was delivered by inhaler at a metered dose of 4000 mg/day (16 puffs) and P was given as one pill, 30 mg/day. Symptoms improved in both groups with no difference in PEF, FEV1 or sputum eosinophil count after 24 hours. Inhaled F versus P produced more rapid initial improvement in some symptoms. Editorís comment: The results support the idea that high-dose inhaled F may be as effective as moderate doses of P to treat asthma exacerbations. Belda J et al. Eur Resp J 2007 [Epub Aug. 9 ahead of print].



这是一个随机临床试验。急诊室就诊的中度支气管哮喘患者45例,19例接受FP安慰剂治疗,而20例接受PF安慰剂治疗。吸烟者与患有严重慢性疾病或四周内曾用皮质激素口服或静脉治疗的患者被排除。F用定量吸入器进行吸入治疗4000毫克/天( 16喷)和P每天一片,30毫克/天。这两组的症状均明显改善。治疗24小时后,峰流速,第一秒用力呼气流速或痰嗜酸性粒细胞计数在两组间无显著性差异。吸入F和口服P相比,某些症状的改善更加迅速。编者按:研究结果支持这样的观点:高剂量吸入F可替代中等剂量P治疗哮喘发作。Belda J et al. Eur Resp J 2007 [Epub Aug. 9 ahead of print].


4. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma.

IL-5 is involved in recruitment, activation and survival of eosinophils, the accumulation of which is associated with AHR and production of inflammatory mediators in asthmatics. This multicenter, randomized, placebo-controlled study sought to determine whether administration of the humanized monoclonal IL-5 antibody, mepolizumab (Mep), to a group of asthmatic patients improved sym- ptom scores, sputum eosinophilia and QOL. The subjects were 18-55 years of age with FEV1 >50% but <80% of predicted and managed by inhaled corticosteroids and beta agonists. Participants were drawn from 55 centers in France, Germany, the Netherlands, UK and US, and 362 patients were randomized into three groups: Mep 250 mg, Mep 750 mg or placebo. Treatments (i.v. injection) were done at baseline (visit three) and twice more at four-week intervals. Efficacy was measured four weeks after the final dose with an eight-week follow-up. Mep injection reduced blood and sputum eosinophils but other outcome measurements were not significantly different from placebo. Editorís comment: While anti-IL-5 therapy for asthma theoretically should be effective, the clinical results are disappointing. Flood-Page P et al. Am J Resp Crit Care Med 2007 [Epub Sept. 13 ahead of print].


mepolizumab治疗中度持续性哮喘患者的安全性及疗效评估白细胞介素5 参与介导嗜酸性粒细胞的趋化活化和存活,在哮喘患者,嗜酸性粒细胞的积聚与气道高反应性和炎性介质的产生相关。在这个多中心-随机-安慰剂对照的临床研究中,研究者试图明确使用mepolizumabMep)这种人化的单克隆白细胞介素5抗体能否改善哮喘患者症状评分,痰嗜酸性粒细胞和生活质量。研究对象年龄为18~55岁,肺功能FEV1大于50%但小于80%预测值,用吸入性类固醇及β受体激动剂治疗哮喘。参加者来自法国,德国,荷兰,英国和美国的55个中心,362例患者随机分为三组:MEP250毫克,MEP750毫克或安慰剂。在基线期(第三次随诊时)进行治疗(静脉注射),并每间隔4周一次再注射两次。最后一次给药4周后进行疗效的评价,并随访8周,MEP注射可降低血和痰嗜酸性粒细胞计数,但其他的参数结果与安慰剂对照无显着差异。编辑按:虽然抗白细胞介素5治疗哮喘理论上应该是有效的,但临床效果令人失望。Flood-Page P et al. Am J Resp Crit Care Med 2007 [Epub Sept. 13 ahead of print].


5. RSV decreases p53 protein to prolong survival of airway epithelial cells.

p53 is a tumor suppressor protein that induces expression of genes for apoptosis and blockade of the cell cycle. When p53 expression is low, as in cancer cells, they do not die. In mice, p53 levels are reduced by murine double minute protein 2 (Mdm2), which causes proteolytic breakdown of p53. RSV infection can increase Mdm2 levels by phosphorylation, and this causes a corresponding decrease in p53 protein and expression of apoptosis genes. The RSV-infected epithelial cells survive longer, but they do not produce more virus. Here, mice were treated with Nutlin-3, an inhibitor of Mdm2, then infected with RSV, and it was found that p53 levels increase and epithelial cells undergo more apoptosis than controls. However, the increased p53 also causes an increase in viral replication and decrease in IL-6. Editorís comment: This paper contributes to the understanding of the complex interaction between RSV and the immune system and may lead the way to the development of new antivirals. Groskreutz DJ et al. J Immunol 2007; 179:2741-2747.



p53基因是一种肿瘤抑制蛋白诱导表达基因,可诱导细胞凋亡,阻断细胞周期。癌细胞中p53蛋白表达低,它们就不会死亡。在小鼠体内,双微粒体蛋白2Mdm2)可降低p53的水平。呼吸道合胞病毒感染可通过磷酸化增加Mdm2水平,这使p53蛋白和细胞凋亡基因的表达相应减少。呼吸道合胞病毒感染的上皮细胞存活更长的时间,但并未造成病毒复制增加。老鼠用抑制mdm2基因的nutlin-3治疗,然后感染呼吸道合胞病毒,发现与对照组比较,p53蛋白水平增加,上皮细胞细胞凋亡增加。不过,增加的p53蛋白也造成病毒复制增加,白细胞介素6生成减少。编者按:本文有助于加深了解呼吸道合胞病毒和免疫系统的之间复杂的相互作用,并可能开辟开发新的抗病毒药物的途径。Groskreutz DJ et al. J Immunol 2007; 179:2741-2747.


6. Pharmacologic rationale for treating allergic and non-allergic rhinitis.

This is an excellent review in the JACI on the subject of the drug treatment of allergic and non-allergic rhinitis. The paper reviews various classifications of rhinitis and algorithms for pharmacologic treatment of allergic and non-allergic rhinitis. It also reviews controversial treatment such as use of intranasal saline and capsaicin. Author's comment: Excellent review, everybody who treats rhinitis should read it. Greiner et al. JACI 2006;118:985.



这是JACI关于过敏性和非过敏性鼻炎药物治疗的一个很好的综述。本文回顾了过敏性鼻炎的分类,并讨论了过敏性和非过敏性鼻炎的药物治疗方案。同时综述了有争议的治疗,例如利用鼻腔生理盐水和辣椒素。作者按:每位治疗鼻炎的临床医生都应该阅读这篇优秀的综述。Greiner, et al. JACI 2006;118:985.


7. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells.

ATP can be released from damaged lung cells during stress and acts upon cells of the immune system via the purine receptors, P2X and P2Y. This paper investigates ATPís potential role in asthma using human bronchoalveolar lavage fluid and a mouse model of allergic asthma. Allergen challenge increases ATP in the lungs accompanied by overexpression of the Th2 cytokines, IL-4, -5 and -13. When ATP is enzymatically neutralized or when the P2 receptors are blocked, airway inflammation is reduced. The authors found that ATP induces expression of a dendritic cell chemoattractant and also directly stimulates maturation of and cytokine production by dendritic cells. Editorís comment: Suppressing purine receptor signaling might be a useful adjunct to asthma therapy. Idzko M et al. Nature Med 2007; 13:913-919.



在应激状态下,被破坏的肺泡细胞可释放出三磷酸腺苷通过嘌呤受体p2Xp2Y作用于免疫系统细胞。本文通过研究人体支气管肺泡灌洗液和小鼠过敏性哮喘模型,考察了三磷酸腺苷在哮喘中的潜在作用。过敏原激发可使肺中的三磷酸腺苷水平升高,并伴随TH2细胞因子(IL-4IL-5IL-13)过度表达。当三磷酸腺苷酶被酶分解或当p2受体受到阻断时,气道炎症减轻。作者发现,三磷酸腺苷诱导树突状细胞趋化因子表达,也直接刺激树突状细胞的成熟,诱导树突状细胞产生细胞因子。编者按:抑制嘌呤受体信号传导可能为哮喘治疗提供的有用的辅助手段。Idzko M et al. Nature Med 2007; 13:913-919.


8. Effects of systemic glucocorticosteroids (GCS) in patients with severe community-acquired pneu- monia (CAP).

The goal of this investigation was to determine the efficacy of GCS in reducing the mortality from CAP. In this retrospective study, 308 elderly patients hospitalized with CAP were evaluated and of that number, 70 had received antibiotics and systemic GCS (equivalent to methylprednisone 24 mg/day or prednisone 30 mg/day). The others received antibiotics alone. The number of deaths among those treated with GCS was significantly reduced compared to those not receiving GCS. Editorís Comment: While this report showed beneficial effects from systemic GCS in elderly patients with CAP, additional studies are needed. Garcia-Vidal C et al. Eur Resp J 2007[Epub Aug. 9 ahead of print].



本项研究的目的是明确全身应用糖皮质类固醇减少重症社区获得性肺炎死亡率的效果。在这个回顾性研究中,对308名社区获得性肺炎老年住院患者进行了评价。在这些患者中,70例接受了抗生素及糖皮质激素全身治疗(相当于甲基强的松龙≥24毫克/天或强的松≥30毫克/天),其他患者只接受了抗生素治疗。接受全身皮质激素治疗患者中,死亡人数明显少于未接受该治疗者。编者按:尽管这份报告显示全身应用糖皮质激素治疗社区获得性肺炎老年患者有效,还需要进一步的研究。Garcia-Vidal C et al. Eur Resp J 2007[Epub Aug. 9 ahead of print].


9. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.

Hyper-IgE syndrome (HIES) is represented by an array of symptoms including skin abscesses, cyst-forming pneumonia, skeletal and dental abnormalities and elevated serum IgE levels. The presence of multi-system effects in HIES suggests that a factor affecting expression of a number of genes might be defective. This study reports that single amino acid changes in the DNA-binding domain of STAT3 are responsible for HIES in 8 out of 15 unrelated non-familial patients. Parents and siblings of the HIES patients as well as a panel of 1000 unrelated healthy controls have the normal STAT3 DNA sequence. The mutant STAT3 is dominant over the normal STAT3 and causes defective responses to IL-6 and IL-10 and reduces DNA binding. Editorís Comment: The com- plexity of HIES is underscored by the observation that there is no difference in overt symptoms between HIES patients with versus those without the STAT3 mutations. Minegishi Y et al. Nature 2007; 448:1058-1062.



IgE综合征(HIES)的临床表现包括皮肤脓肿、囊肿形成性肺炎、骨骼和牙齿异常、血清IgE水平升高。HIES对多系统都有影响,这表明可能存在某种控制多个基因表达的因素。根据这项研究,15个无血缘关系的非家族性HIES患者中8例出现STAT3 DNA结合区单氨基酸的突变,这种突变是导致HIES的原因。HIES患者的父母和兄弟姐妹及1000名无血缘关系的健康对照组的STAT3 DNA序列均正常。相对正常STAT3,突变的STAT3是显性的,可导致对白细胞介素-6和白细胞介素10 的免疫反应减弱,并减少脱氧核糖核酸的结合。编者按:本研究强调了HIES的复杂性,因本观察中有STAT3突变和没有STAT3突变患者间,在HIES显性症状方面无显著性差异。Minegishi Y et al. Nature 2007; 448:1058-1062.


10. IgE-antibody-dependent immunotherapy of solid tumors: Cytotoxic and phagocytic mechanisms of eradication of ovarian cancer cells.

The use of tumor-specific Abs to target cancer cells for destruction is a promising avenue of research, and this report demonstrates that the IgE isotype may be more effective than IgG in treating sarcomas. Human ovarian cancer cells in culture were exposed to human peripheral blood monocytes (PBMCs) in combination with IgE Ab against folate-binding protein, an ovarian cancer- specific marker. Three-color flow cytometry analysis shows that Ab-activated monocytes kill tumor cells by both cytotoxic means and phagocytosis. In vivo experiments utilized nude mice injected with ovarian cancer cells with or without PBMCs and Ab. IgE Ab treatment results in enhanced cancer cell killing in vitro and increased survival of mice injected i.p. with ovarian cancer cells. The report also elucidates the mechanism of tumor cell killing by monocytes and demonstrates that a tumor-specific IgE Ab can direct eosinophils to kill ovarian cancer cells. Editorís comment: This report offers hope for an improved treatment strategy utilizing tumor-specific IgE Abs. Karagiannis SN et al. J Immunol 2007; 179:2832-2843.



利用肿瘤特异性抗体针对癌细胞的靶向杀伤是一项很有前途的研究,这份报告表明IgE型抗体可能比IgG型抗体能更加有效地治疗肉瘤。培养的人类卵巢癌细胞暴露于外周血单核细胞(PBMCS),同时使用卵巢癌特异性标志物叶酸结合蛋白的IgE抗体。三色流式细胞仪分析表明,抗体活化的单核细胞可以通过细胞毒性和吞噬作用杀死肿瘤细胞。在体内实验中,给裸鼠注射卵巢癌细胞,然后用或不用PBMCS以及抗体处理。IgE治疗加强了体外癌细胞杀伤,增加腹腔注射卵巢癌细胞小鼠的存活率。该报告还阐明了单核细胞杀死肿瘤细胞的机制,并显示肿瘤特异性IgE抗体可引导嗜酸性粒细胞杀死卵巢癌细胞。编者按:该报告指出有望利用肿瘤特异性IgE抗体治疗肿瘤。Karagiannis SN et al. J Immunol 2007; 179:2832-2843.


11. IL-13 regulates cilia loss and foxj1 expression in human airway epithelium.

Defects in mucociliary clearance in the lung lead to mucus plugging and impaired clearance of microbes and particulates. These defects can result from RSV infection which causes loss of ciliated epithelial cells and excess mucus production in RSV-infected infants and asthmatics. This report examines the mechanism of ciliary loss and repair using cultured human airway epithelium. Treatment of cells with IL-13 results in 65-90% loss of ciliated cells and downregulation of the transcription factor, foxj1, which is necessary for cilia formation. The fact that IL-13 is elevated in asthma and respiratory infections suggests that it may be the instigator of ciliated epithelial cell loss. Editorís Comment: An additional observation is the potential trans-differentiation of ciliated epithelial cells to mucous cells, which supports the idea of cellular plasticity in airway epithelium. Gomperts BN et al. Am J Resp Cell Mol Biol 2007; 37:339-346.



肺黏液纤毛清除功能缺陷,可导致黏液栓形成并削弱微生物和微粒的清除。在呼吸道合胞病毒感染婴儿和哮喘患者中,这些缺陷而造成纤毛上皮细胞受损及黏液过度产生。本研究用培养的人呼吸道上皮细胞研究纤毛受损和修复机制。经白细胞介素-13治疗的细胞纤毛细胞受损率为65%~90%,且纤毛形成过程中必要的foxj1转录因子下调。而哮喘和呼吸道感染者白细胞介素-13水平升高,表明其可能是导致人纤毛上皮细胞受损的帮凶。编者按:一个额外的发现是,纤毛上皮细胞有可能转分化为黏液细胞,它支持了气道上皮细胞可塑性的观点。Gomperts BN et al. Am J Resp Cell Mol Biol 2007; 37:339-346.


译者:北京协和医院 文利平†††

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The World Allergy Organization (WAO) Web Site supports the WAO mission. WAO is a global resource and advocate in the field of allergy, asthma and clinical immunology, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies. 

The WAO website is an up-to-date compendium of information about allergy, asthma and immunology for all physicians, including specialists, other health care professionals and patients.  It also provides a network for global contacts in the field. 

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世界过敏组织(WAO)网站支持WAO使命。 WAO是全球性资源中心,过敏、哮喘和临床免疫学领域的提倡者,通过全世界过敏和临床免疫学会联盟推进过敏性疾病的最佳临床治疗、教育、研究和培训。





1. 每月一次更新的WAO新闻和纪要,被翻译成七种语言,从大约15本主要专业杂志中摘取的文献摘要,公布会议教育资源、新书评论

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Made possible through an unrestricted educational grant from Novartis.

Translator: Liping Wen MD Peking Medical College Hospital†† 译者:北京协和医院变态反应科 文利平