奥马珠单抗对过敏性哮喘患者血清细胞因子谱的影响

doi:10.16138/j.1673-6087.2023.06.003

摘要/Abstract

摘要：

目的：探讨奥马珠单抗对过敏性哮喘患者血清细胞因子谱的影响。方法：纳入2019年1月至2021年1月在上海交通大学医学院附属瑞金医院呼吸与危重症医学科就诊并接受奥马珠单抗治疗的过敏性哮喘患者20例。收集奥马珠单抗治疗前及治疗4个月后患者肺功能数据，评估肺功能改善状况；采用电化学发光免疫分析法测定奥马珠单抗治疗前后患者血清中29个细胞因子水平，并比较其治疗前后的变化；采用哮喘控制测试（asthma control test，ACT）问卷评估哮喘控制改善状况；采用全球治疗有效性评估（global evaluation of treatment effectiveness，GETE）评分评估治疗有效性。结果：20例患者接受奥马珠单抗治疗4个月后，肺功能中平均用力呼出50%肺活量呼气流速（maximal expiratory flow at 50% of forced vital capacity，MEF50%）显著改善（P<0.05）；血清中辅助性T17细胞（helper T17 cell, Th17细胞）相关因子白细胞介素（interleukin，IL）-17A及IL-23水平显著上升（P<0.05），其余因子水平的改变差异无统计学意义；治疗后哮喘控制情况显著改善（P<0.01）；根据GETE评分，17例患者显效，3例不显效。结论：过敏性哮喘患者接受奥马珠单抗治疗后哮喘控制情况显著改善；Th17相关因子水平的上升及Th17细胞功能的恢复可能是奥马珠单抗的潜在治疗机制之一。

关键词: 奥马珠单抗, 过敏性哮喘, 细胞因子

Abstract:

Objective To investigate the effect of omalizumab on serum cytokine profile in the patients with allergic asthma. Methods A total of 20 patients with allergic asthma who received omalizumab treatment in the Department of Pulmonary and Critical Care Medicine of Ruijin Hospital were enrolled in this study. Data of spirometry test was collected before and after 4 months of omalizumab treatment to evaluate the improvement of lung function. Serum samples before and after 4 months of omalizumab treatment were collected to measure 29 cytokines using Meso Scale Discovery(MSD). Asthma control was assessed by asthma control test (ACT) score and treatment effectiveness was evaluated by the Global Evaluation of Treatment Effectiveness (GETE) score. Results After 4 months of omalizumab treatment, maximal expiratory flow at 50% of forced vital capacity (MEF50) was significantly improved among 20 patients (P<0.05). Serum interleukin(IL)-17A and IL-23 levels were significantly increased(P<0.05). Asthma control was significantly improved(P<0.01). According to GETE score, omalizumab treatment was effective in 17 patients, but not effective in 3 patients. Conclusions Omalizumab treatment effectively improves asthma control in allergic asthmatics. Increased levels of helper T17 (Th17) cell -related cytokines and recovery of Th17 cell function may be one of the potential therapeutic mechanisms of omalizumab.

Key words: Omalizumab, Allergic asthma, Cytokines

中图分类号:

R562.25

郑晓燕, 孙璘, 汤葳. 奥马珠单抗对过敏性哮喘患者血清细胞因子谱的影响[J]. 内科理论与实践, 2023, 18(06): 388-393.

ZHENG Xiaoyan, SUN Lin, TANG Wei. Effect of omalizumab treatment on serum cytokine profile in allergic asthma patients[J]. Journal of Internal Medicine Concepts & Practice, 2023, 18(06): 388-393.

图/表 4

表1

表2

奥马珠单抗治疗前后患者血清细胞因子谱的变化比较[均n=20，M(P25, P75), ng/L]

细胞因子	治疗前	治疗后	P
Th1相关因子
IFN-γ	8.614 (6.316，12.230)	9.836 (7.858，14.910)	>0.05
IP-10	200.1 (136.6，222.7)	180.7 (125.3，236.6)	>0.05
TNF-β	1.757 (1.279，1.912)	1.761 (1.476，2.063)	>0.05
IL-18	406.3 (299.3，581.2)	475.3 (282.9，542.7)	>0.05
Th2相关因子
IL-4	0.048 (0.060，0.076)	0.064 (0.052，0.078)	>0.05
IL-5	0.800 (0.589，1.257)	0.733 (0.522，1.251)	>0.05
IL-6	0.973 (0.679，1.263)	0.918 (0.634，1.454)	>0.05
IL-13	3.517 (3.100，4.500)	3.868 (2.848，4.831)	>0.05
IL-31	8.802 (2.855，11.11)	10.29 (7.316，14.85)	>0.05
TARC	251.9 (138.8，336.8)	263.3 (157.2，348.9)	>0.05
Th9相关因子
IL-9	0.343 (0.148，0.581)	0.355 (0.264，0.715)	>0.05
Th17相关因子
IL-17A	2.677 (1.439，4.603)	3.953 (3.304，5.173)	<0.05
IL-21	2.773 (1.950，4.286)	3.840 (2.379，5.146)	>0.05
IL-22	0.577 (0.440，0.919)	0.840 (0.578，1.140)	>0.05
IL-23	0.461 (0.033，1.097)	1.112 (0.850，2.069)	<0.05
Treg相关因子
IL-10	0.430(0.352，0.560)	0.408 (0.279，0.655)	>0.05
单核细胞相关因子
IL-27	583.2 (360.4，1111)	668.1 (420.9，1186)	>0.05
IL-1β	0.280 (0.187，0.485)	0.365 (0.194，0.568)	>0.05
MCP-1	205.9 (148.2，252.6)	203.1 (160.2，265.1)	>0.05
MCP-2	47.9 (40.0，57.0)	47.3 (40.7，54.3)	>0.05
MCP-3	6.3 (4.5，7.1)	6.1 (4.4，8.2)	>0.05
MCP-4	135.0 (78.1，166.3)	120.1 (93.9，240.0)	>0.05
嗜酸性粒细胞相关因子
Eot-1	163.6 (125.5，252.7)	187.6 (129.7，302.2)	>0.05
Eot-2	1 776.0 (1 276.0，2 321.0)	1 637.0 (863.4，2 178.0)	>0.05
Eot-3	30.3(25.0，56.5)	35.6 (29.1，68.6)	>0.05
气道重构相关因子
VEGF-A	96.3(73.6，150.3)	115.1 (72.0，182.7)	>0.05
SDF-1α	836.6 (740.5，1 101.0)	920.5 (769.4，1 150.0)	>0.05
YKL-40	36 258 (30 525，51 378)	31 198 (21 362，63 064)	>0.05
TRAIL	111.3 (89.1， 131.8)	133.9 (112.8，160.3)	>0.05

表2

图1

表3

参考文献 20

[1]	Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases[J]. J Allergy Clin Immunol, 2003, 112(2):252-262. doi: 10.1067/mai.2003.1595 URL
[2]	Afshar R, Medoff BD, Luster AD. Allergic asthma: a tale of many T cells[J]. Clin Exp Allergy, 2008, 38(12): 1847-1857. doi: 10.1111/j.1365-2222.2008.03119.x pmid: 19037961
[3]	Palomares Ó, Sánchez-Ramón S, Dávila I, et al. Divergent: how IgE axis contributes to the continuum of allergic asthma and anti-IgE therapies[J]. Int J Mol Sci, 2017, 18(6): 1328. doi: 10.3390/ijms18061328 URL
[4]	Davis LA. Omalizumab: a novel therapy for allergic asthma[J]. Ann Pharmacother, 2004, 38(7-8): 1236-1242. pmid: 15187202
[5]	Okayama Y, Matsumoto H, Odajima H, et al. Roles of omalizumab in various allergic diseases[J]. Allergol Int, 2020, 69(2): 167-177. doi: S1323-8930(20)30010-1 pmid: 32067933
[6]	Pelaia C, Calabrese C, Terracciano R, et al. Omalizumab, the first available antibody for biological treatment of severe asthma: more than a decade of real-life effectiveness[J]. Ther Adv Respir Dis, 2018, 12: 1753466618810192.
[7]	Solèr M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics[J]. Eur Respir J, 2001, 18(2):254-261. doi: 10.1183/09031936.01.00092101 pmid: 11529281
[8]	中华医学会呼吸病学分会哮喘学组. 奥马珠单抗治疗过敏性哮喘的中国专家共识(2021版)[J]. 中华结核和呼吸杂志, 2022, 45(4): 341-354.
[9]	Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control[J]. J Allergy Clin Immunol, 2004, 113(1):59-65. doi: 10.1016/j.jaci.2003.09.008 URL
[10]	Bousquet J, Humbert M, Gibson PG, et al. Real-world effectiveness of omalizumab in severe allergic asthma[J]. J Allergy Clin Immunol Pract, 2021, 9(7): 2702-2714. doi: 10.1016/j.jaip.2021.01.011 URL
[11]	Yalcin AD, Uzun R. Anti-IgE significantly changes circulating interleukin-25, vitamin-D and interleukin-33 levels in patients with allergic asthma[J]. Curr Pharm Des, 2019, 25(35): 3784-3795. doi: 10.2174/1381612825666190930095725 URL
[12]	Sellitto A, De Fanis U, Balestrieri A, et al. Effects of omalizumab treatment on serum cytokine concentrations of atopic patients with chronic spontaneous urticaria[J]. Eur Ann Allergy Clin Immunol, 2017, 49(4): 171-175. doi: 10.23822/eurannaci.1764-1489.10 pmid: 28752720
[13]	Minegishi Y, Saito M. Molecular mechanisms of the immunological abnormalities in hyper-IgE syndrome[J]. Ann N Y Acad Sci, 2011, 1246: 34-40. doi: 10.1111/nyas.2011.1246.issue-1 URL
[14]	Knochelmann HM, Dwyer CJ, Bailey SR, et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity[J]. Cell Mol Immunol, 2018, 15(5): 458-469. doi: 10.1038/s41423-018-0004-4 pmid: 29563615
[15]	Boonpiyathad T, Sözener ZC, Satitsuksanoa P, et al. Immunologic mechanisms in asthma[J]. Semin Immunol, 2019, 46: 101333.
[16]	Ogawa R, Suzuki Y, Kagawa S, et al. Distinct effects of endogenous interleukin-23 on eosinophilic airway inflammation in response to different antigens[J]. Allergol Int, 2015, 64 Suppl: S24-S29.
[17]	Moreira AP, Cavassani KA, Ismailoglu UB, et al. The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A[J]. J Clin Invest, 2011, 121(11): 4420-4432. doi: 10.1172/JCI44999 pmid: 22005301
[18]	Djukanović R, Wilson SJ, Kraft M, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma[J]. Am J Respir Crit Care Med, 2004, 170(6): 583-593. doi: 10.1164/rccm.200312-1651OC URL
[19]	Noga O, Hanf G, Brachmann I, et al. Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma[J]. J Allergy Clin Immunol, 2006, 117(6): 1493-1499. doi: 10.1016/j.jaci.2006.02.028 URL
[20]	Huang YC, Weng CM, Lee MJ, et al. Endotypes of severe allergic asthma patients who clinically benefit from anti-IgE therapy[J]. Clin Exp Allergy, 2019, 49(1): 44-53. doi: 10.1111/cea.2019.49.issue-1 URL

时间	治疗前	治疗后	P
FVC%	79.29±17.88	83.89±16.06	>0.05
FEV₁%	63.00±21.35	70.04±21.75	>0.05
FEV₁/FVC%	77.54±16.52	82.69±16.98	>0.05
MEF75%	44.98（29.33，73.58）	51.04（31.65，72.47）	>0.05
MEF50%	33.93（23.06，73.03）	40.10（22.90，60.84）	<0.05
MEF25%	30.77（21.99，57.43）	30.03（17.87，54.11）	>0.05