哮喘变应原免疫治疗现状与思考.ppt

1、,哮喘变应原免疫治疗现状与思考,上海交通大学医学院苏州九龙医院 倪殿涛,过敏性疾病作为一个全球性问题,WAO White Book on Allergy 2011-2012,A steady increase in the prevalence of allergic diseases globally has occurred with about 30-40% of the world population now being affected by one or more allergic conditions,Types of allergies,Allergen,Anysubstan

2、ce oftenaproteinthatinducesanallergy Common allergens,过敏原种类很多 “除了水、 葡萄糖和盐之外 都可以成为过敏原”,Common cold or allergy,Asthma,Derived from the Greek root Originally did not define a disease, but was employed to describe respiratory symptoms of a variety of pulmonary conditions By the beginning of the 20th cen

3、tury,asthmawas seen to be a unique illness characterized by spasmodic afflictions of the bronchial tubes. Today,asthmais seen as a chronic inflammatory disease which is not yet fully understood in its pathophysiology Therapy is still on the path to becoming optimal.,Bergmann KC.Asthma.Chem Immunol A

4、llergy. 2014;100:69-80.,盲人摸象,2014 GINA哮喘表型,Allergic asthma: usually respond well to inhaled corticosteroid(ICS) treatment Non-allergic asthma: often respond less well to ICS. Late-allergic asthma: some adults, particularly women, patient with asthma for the first time in a dult life. These patients

5、tend to be non-allergic, and often require higher doses of ICS or are relatively refractory to corticosteroid treatment Asthma with fixed airflow limitation: some patients with long-standing asthma develop fixed airflow limitation that is thought to be due to airway wall remodeling. Asthma with obes

6、ity: some obese patients with asthma have prominent respiratory symptoms and little eosinophilic airway inflammation.,GINA Guidelines for Asthma 2014,Terminology of allergic phenomena,idiosyncrasy - antipathy - Hypersensitivity -Anaphylaxis -allergy A.F. Coca and R.A. Cooke introduced the term atopy

7、：hypersensitiveness occurred spontaneously atopy gained a new sense, since IgE is a characteristic - Clinically similar diseases such as asthma, rhinoconjunctivitis or eczema can be found in the absence of IgE, and are then called intrinsic variants of the same disease,Chem Immunol Allergy. 2014;100

8、:46-52.,Coombs and Gells Classification of Hypersensitivity,Does intrinsic asthma exist?,Ten to forty percent of asthmatics are intrinsic Analysis of bronchial mucosal expression of pro-eosinophilic and pro-atopic markers IL-3, -4, -5, -13, GM-CSF, RANTES, MCP-3, IgE and high affinity IgE receptor (

9、Fc epsilon RI) There were more similarities than differences in immunopathology between atopic and nonatopic,Humbert M.Does intrinsic asthma exist?Rev Mal Respir. 2000 Feb;17(1 Pt 2):245-54.,Allergic vs nonallergic asthma: what makes the difference?,Nonallergic：Greater age, female sex, sinusal polyp

10、osis, and FEV1 below 80% of the predicted value Allergic：history of hay fever, seasonal exacerbation of asthma, and asthma duration,Allergy. 2002 Jul;57(7):607-13.,Asthma phenotypes: nonallergic (intrinsic) asthma.,The definition ：subjects with asthma and with whom allergic sensitization cannot be d

11、emonstrated negative skin prick test or in vitro specific-IgE test to a panel of seasonal and perennial allergens Nonallergic asthma occurs in 10% to 33% of individuals with asthma and has a later onset than allergic asthma, with a female predominance. Nonallergic asthma appears to be more severe th

12、an allergic asthma in many cases and may be less responsive to standard therapy,Peters SP. Asthma phenotypes: nonallergic (intrinsic) asthma. J Allergy Clin Immunol Pract.2014 Nov-Dec;2(6):650-2.,Novel diagnostic approaches and biological therapeutics for intrinsic asthma.,Controversies have emerged

13、 in relation to this concept Not finding specific allergen sensitization in an asthmatic patient neither excludes an allergic component nor the essential role that immunoglobulin E may play in asthma The atopic status is one among many other questions Omalizumab, the only monoclonal anti-immunoglobu

14、lin E antibody commercialized for asthma, should be tried in patients with uncontrolled severe asthma independent of their atopic status,Vennera Mdel C1,Picado C1.Novel diagnostic approaches and biological therapeutics for intrinsic asthma.Int J Gen Med.2014Jul 8;7:365-71.,哪些哮喘患者需要行AIT？,过敏的概念 总tIgE,

15、Senti et al Allergy 2011;66(6):798,1911 Noon 1th SCIT 1950s 1th SCIT Control Study; 1980s 1th DBPC SLIT; 2000s 1th sublingual Tablet 2011s Innovating for patient benefit,100 yeas of antigen specific immunotherpy,Allergen specific immunotherapy,Self-amplification mechanisms of mast cell activation: a

16、 new look in allergy.,The current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all allergens mentioned above can activate these

17、 cells we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions whereas IgE only serves as one of the activators of these cells.,He S, Zha

18、ng H, Zeng X, Yang P.Curr Mol Med. 2012 Dec;12(10):1329-39.,过敏性疾病实验室诊断的理想程序,皮试、斑贴试验 （阳性） 过敏原、半抗原或小分子物质 嗜碱性粒细胞/肥大细胞激发试验 （阳性）（阴性基本排除急性过敏） 特异性IgE 、IgG 检测 （阴性） （阳性） （阳性） 类过敏反应 IgE依赖性 IgG依赖性 （目前定义为过敏）（目前定义为食物不耐受） 避免接触类过敏原 （IgG阳性） 脱敏疗法的适应症 低敏食物、食物脱敏？,AIT适应症-中国专家共识,AIT禁忌症-中国专家共识,哮喘患者AIT现状,结 论,Sublingual im

19、munotherapy,Included 5,131 patients from 63 studies were analyzed that sublingual immunotherapy improves symptoms of asthma reduces the use of asthma medications improves the quality of life,Lin et al.Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic

20、 review. JAMA 2013;309:1278-88,AIT的安全性,哮喘AIT困惑与思考,过敏原识别,过敏原的特异性诊断 查找过敏原是与其他学科的基本区别,IgE介导变态反应的诊断,Allergic rhinitis and its impact on asthma Allergy, 2008,s1-153.,体内试验-皮肤试验,皮内试验 I型速发性变态反应 点刺试验 I型速发性变态反应 斑贴试验 IV型迟发型变态反应,常用过敏原点刺液种类,螨属：户尘螨、粉尘螨、热螨、仓储螨 宠物毛发皮屑：猫毛、狗毛 树木花粉：桤木、榛属、杨属、榆科、柳属、悬铃木 杂草花粉：蒿草、豚草、葎草、鸡足草

21、、酥油草、毒麦、梯牧草、牧场草 作物花粉：向日葵、玉米 真菌：链格孢、毛壳菌、芽枝霉、镰刀菌、青霉、扩展青霉、点青霉 蟑螂：德国小蠊、美洲大蠊,体外试验-sIgE检测,严重皮炎不能作皮试者 皮试假阳性的划痕症患者 皮肤反应差的老年人及3岁以下儿童 用药的影响 严重过敏状态发作者 对作皮试时产生的不适恐惧者 对过敏严重度评估 拟行特异性免疫治疗者,我国过敏原体外诊断种类,RAST-放射过敏原吸附试验 FEIA-固相荧光酶免疫技术（CAP） 免疫印迹技术（AS） ELISA-酶联免疫吸附试验 免疫捕获法（酶联免疫吸附试验中之一种） 过敏原芯片：固相液相 免疫化学发光法 过敏原诱发组胺释放试验：期望

22、能解决IgE不能解决的问题,五种免疫球蛋白的血浆浓度（mg/dL）,IgG 1200 （40000） IgM 150 （5000） IgA 300 （10000） IgD 3 （100） IgE 0.03 （1） 血中IgE含量甚微，仅为血中IgG的四万分之一 特异性IgE含量则更甚微,一般的免疫学方法测不到sIgE,放射过敏原吸附试验(RAST) 荧光免疫标记分析法 ELISA（酶联免疫吸附测定） 蛋白芯片检测 荧光酶免法（ImmunoCAP Sweden）是检测的金标准,总IgE的意义,总IgE没有正常值，只定上限端值，儿童50KU/L 成人60KU/L 新生儿的总IgE很低，随年龄增长升高，10-15岁达顶峰，以后又逐步下降，男性高于女性 理想的情况下，总IgE应该是0或极低,对总IgE的认识,总IgE=【各种特异性IgE】【其它因素】 影响总IgE水平其它因素 年龄 性别 种族 寄生虫感染 最重要，在农村寄生虫高发区总IgE的水平可能很高,总IgE升高的意义,总IgE升高提示存在过敏可能性，生活水平越高，寄生虫感染率越低，总IgE越能反映过敏状态 总IgE升高与皮肤试验及sIgE阳性率存在相关性 总IgE高不一定就是过敏！,可导致总IgE升高的疾病,过敏性疾病 免疫性疾病：选择性IgA缺乏症 感染：寄生虫、霉菌、病毒 肿瘤：骨