變應(yīng)原免疫治療進(jìn)展

1、變應(yīng)原免疫治療研究進(jìn)展The progress of Allergen Immunotherapy research重慶新橋醫(yī)院程曉明Mar 27th 2016 重慶.變應(yīng)性疾病-如影相隨Gupta R, et al. BMJ. 2003 Nov 15x;327(7424):1142-3Ninan TK, et al. BMJ. 1992 Apr 4;304(6831):873-5.歷史變遷Larch M, et al. Nat Rev Immunol. 2006;6(10):761-71Von Pirquet.是Specific Immunotherapy (SIT) 還是Allergen

2、Immunotherapy (AIT)?Caldern MA, et al. Allergy. 2013;68(7):825-8.AIT的機(jī)制是什么？Akdis CA, et al. World Allergy Organ J. 2015;8(17): 1-12. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens.Very early basophil tolerance :Early decrease in mast cell and basophil activity for sy

3、stemic anaphylaxisType I skin test reactivityEarly increase in specific IgE followed by a late decrease in specific IgEIncrease in specific IgG4 and in some studies IgA and IgG1Decreased numbers of tissue mast cells and eosinophils and release of their mediators in nasal mucosal biopsies of allergic

4、 rhinitis patientsDecreased skin late-phase response in parallel to decreased lymphocyte and eosinophil infiltrationInduction of Treg and Breg cells suppression of Th2-Th1 cells.AIT可能的推手-Treg和BregAkdis CA, et al. World Allergy Organ J. 2015;8(17): 1-12. Mechanisms of allergen-specific immunotherapy

5、and immune tolerance to allergens.PharmacotherapyAllergen avoidanceAllergen immunotherapyPatient education變應(yīng)變應(yīng)性性疾病綜合治療方案疾病綜合治療方案Bousquet J, et al. J Allergy Clin Immunol. 1998;102(4 Pt 1):558-62 Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper.內(nèi)容內(nèi)容建議建議推薦強(qiáng)度推薦強(qiáng)度

6、環(huán)境因素那些明確因環(huán)境變應(yīng)原致病的患者應(yīng)避免接觸已知變應(yīng)原或進(jìn)行環(huán)境控制（不養(yǎng)寵物、使用過(guò)濾系統(tǒng)、防螨罩或殺螨劑）可選Seidman MD, et al. Otolaryngol Head Neck Surg. 2015;152(1 Suppl):S1-43.GINA和NAEPP關(guān)于環(huán)境控制的建議 GINA 2014N Engl Med 2009; 360:1862-9. AIT對(duì)蜂毒過(guò)敏反應(yīng)、過(guò)敏性鼻炎/結(jié)膜炎，過(guò)敏性哮喘有效 免疫治療是唯一可以影響變應(yīng)性疾病自然病程的治療方法，它還可阻止變應(yīng)性鼻炎發(fā)展為哮喘 成功的免疫治療取決于標(biāo)準(zhǔn)化的、可持續(xù)生產(chǎn)的高質(zhì)量變應(yīng)原疫苗10Bousquet J

7、, et al. J Allergy Clin Immunol. 1998;102(4 Pt 1):558-62.200620112012.歐美AIT現(xiàn)狀Burks AW, et al. J Allergy Clin Immunol. 2013;131(5):1288-96.變應(yīng)原配方 療效：由于研究設(shè)計(jì)的多樣性，使得比較困難 總結(jié)：只給患者接種引起癥狀的變應(yīng)原Nelson HS et al. J Allergy Clin Immunol. 2009; 123: 763-769美國(guó) 多種變應(yīng)原混合物（平均8種）歐洲 一般為1種。2種及以上10%.脫敏途徑-SCIT或SLIT 歐洲：SLIT占A

8、IT的45% ，區(qū)域差別大（北歐限新EMA注冊(cè)變應(yīng)原，德國(guó)25%，南歐80%） 美國(guó)：2014年4月FDA批準(zhǔn)3種舌下片劑傳統(tǒng)治療：SCIT.對(duì)AIT療效的共識(shí)-過(guò)敏性疾病修飾劑Committee for Medicinal Products for Human Use (CHMP) and Efficacy Working Party (EWP) 預(yù)防變應(yīng)性鼻炎并發(fā)哮喘 預(yù)防對(duì)新變應(yīng)原過(guò)敏 停用后保持長(zhǎng)期臨床效果.真實(shí)世界AIT對(duì)預(yù)防鼻炎進(jìn)展為哮喘的肯定作用 -6年回顧性研究Schmitt J, et al. J Allergy Clin Immunol. 2015 Dec;136(6):1

9、511-6 RA患者進(jìn)行AIT發(fā)生哮喘的危險(xiǎn)顯著低于非AIT SCIT的預(yù)防作用顯著 天然提取物制備的變應(yīng)原作用顯著 3年和更久的治療作用顯著.對(duì)AIT現(xiàn)狀的共識(shí)-適應(yīng)癥適應(yīng)癥：同時(shí)罹患哮喘和鼻炎 變應(yīng)性鼻炎 藥物不能控制癥狀 嚴(yán)重藥物不良反應(yīng) 不愿長(zhǎng)期用藥 .對(duì)AIT現(xiàn)狀的共識(shí)-操作指南1. 適應(yīng)癥2. 禁忌癥3. 治療后觀察30mins4. 妊娠期AIT5. -阻滯劑的使用6. 人員培訓(xùn)7. 醫(yī)療器械準(zhǔn)備8. 醫(yī)療文件準(zhǔn)備.對(duì)AIT現(xiàn)狀的共識(shí)-低估AIT的治療價(jià)值盡管均認(rèn)為AIT是唯一對(duì)哮喘和鼻炎起到修飾作用的治療，目前僅5%患者接受AIT 療效證據(jù)不充分 支出-獲益比不明確 從業(yè)醫(yī)生水準(zhǔn)

10、和認(rèn)知水平不一 普通人群對(duì)AIT常識(shí)少 患者害怕治療方案或藥品申請(qǐng)過(guò)程 入選病例的差異(level D) -GINA 2015Jutel M, et al. J Allergy Clin Immunol. 2015;136(3):556-68.未來(lái)關(guān)注標(biāo)準(zhǔn)化研究變應(yīng)原標(biāo)準(zhǔn)化安全性分子診斷技術(shù).研究標(biāo)準(zhǔn)化Canonica GW, et al. Allergy. 2007;62(3):317-24Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respir

11、atory allergy. A statement of a World Allergy Organization (WAO) taskforce 1911年SCIT首次應(yīng)用于臨床，1960年發(fā)表首個(gè)雙盲安慰劑對(duì)照（DBPC）療效觀察的臨床研究，SLIT的DBPC在1986年。 方法學(xué)缺陷：樣本小 退出率高 組間疾病嚴(yán)重程度不匹配 變應(yīng)原效價(jià)無(wú)法比較 單獨(dú)癥狀評(píng)價(jià)或用藥評(píng)分William Frankland (1912-) AIT 100年紀(jì)念.變應(yīng)原標(biāo)準(zhǔn)化 美國(guó)FDA生物檢測(cè)研究中心CBER(center for biologics evaluation and research)標(biāo)準(zhǔn)化和

12、非標(biāo)準(zhǔn)化制劑 歐洲歐洲藥物局（EMA）統(tǒng)一審查認(rèn)證變應(yīng)原工業(yè)化生產(chǎn)，新產(chǎn)品進(jìn)行注冊(cè).Jutel M, et al. J Allergy Clin Immunol. 2015;136(3):556-68Cox L, et al. J Allergy Clin Immunol. 2011;127(1 Suppl):S1-55Wheatley LM, et al. N Engl J Med. 2015 Jan 29;372(5):456-63 單一變應(yīng)原效果肯定It is not know whether multi-allergen therapy results in better outcom

13、es than single-allergen therapy. Althrough some older studies suggest a benefit of multi-allergen immunotherapy, most trails showing the efficacy of immunotherapy involve a signle allergen.-Clinical practice. Allergic rhinitis -Allergen immunotherapy: a practice parameter third updateSummary Stateme

14、nt 72: There are few studies that investigated the efficacy of multiallergen subcutaneous immunotherapy. These studies have produced conflicting results, with some demonstrating significant clinical improvement compared with placebo and others showing no benefit over optimal pharmacotherapy and envi

15、ronmental control measures. Thus it is important to treat the patients only with relevant allergens. ( B ) 變應(yīng)原種類：強(qiáng)調(diào)使用主要變應(yīng)原.AIT的安全性 SCIT: 注射部位充血、腫脹、瘙癢（85%） 全身反應(yīng)：1次注射 致命過(guò)敏反應(yīng)：1/100萬(wàn)次注射 SLIT：口咽瘙癢、腫脹（ 75%） 無(wú)致命過(guò)敏反應(yīng)Wheatley LM, et al. Clinical practice. Allergic rhinitis. N Engl J Med. 2015; 372(5): 456-63

16、.減少SCIT風(fēng)險(xiǎn)Epstein TG. J Allergy Clin Immunol Pract. 2014 ;2(2):161-7. 哮喘未控制、重癥哮喘是導(dǎo)致嚴(yán)重不良反應(yīng)的主要原因哮喘未控制、重癥哮喘是導(dǎo)致嚴(yán)重不良反應(yīng)的主要原因 措施1 每次治療前進(jìn)行哮喘控制評(píng)估2 遵循標(biāo)準(zhǔn)操作規(guī)范3 花粉季調(diào)整劑量4 避免集群免疫治療.分子診斷技術(shù)的應(yīng)用Molecular-based allergy (MA) diagnostics 鑒別多重過(guò)敏患者真正的致敏源 真正的變應(yīng)原 vs 交聯(lián)反應(yīng) （泛變應(yīng)原） 減少食物過(guò)敏診斷的風(fēng)險(xiǎn) 穩(wěn)定的變應(yīng)原分子 vs 易變的變應(yīng)原分子 可能提高AIT的療效 Canonica GW, et al