Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease.
Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease.
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DOI：
10.1016/j.jaci.2021.05.043
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发表时间：
2021-08
影响因子：
14.2
通讯作者：
Laidlaw, Tanya M.
中科院分区：
文献类型：
--
作者：
Buchheit, Kathleen M.;Lewis, Erin;Gakpo, Deborah;Hacker, Jonathan;Sohail, Aaqib;Taliaferro, Faith;Giron, Evans Berreondo;Asare, Chelsea;Vukovic, Marko;Bensko, Jillian C.;Dwyer, Daniel F.;Shalek, Alex K.;Ordovas-Montanes, Jose;Laidlaw, Tanya M.
关键词：
嗜酸性粒细胞性哮喘和鼻息肉病是阿司匹林加重的呼吸道疾病（AERD）的标志，IL-5抑制剂已显示出治疗益处。然而，除嗜酸性粒细胞外，IL-5 R α还在许多细胞上表达，IL-5抑制导致嗜酸性粒细胞性哮喘和鼻息肉病临床获益的机制不太可能完全是由于抗嗜酸性粒细胞作用。我们试图确定美泊利单抗IL-5治疗改善AERD呼吸道炎症的机制。对18例接受美泊利珠单抗治疗的AERD受试者的临床特征、循环粒细胞、鼻刮成绩单、嗜酸性阳离子蛋白、类胰蛋白酶、抗体水平以及尿和鼻类花生酸水平进行了测定，并与18例未接受美泊利珠单抗治疗的匹配AERD受试者进行了比较。接受美泊利珠单抗治疗的受试者外周血嗜酸性粒细胞和嗜碱性粒细胞显著减少，并且那些保留的细胞的表面CRTH 2表达高于未接受美泊利珠单抗治疗的受试者。美泊利珠单抗组受试者的鼻前列腺素（PG）F2α、PGD 2代谢产物、白三烯（LT）B4和血栓烷水平较低，尿四去甲-PGD 2和LTE 4水平也较低。在接受美泊利珠单抗治疗的AERD受试者中，鼻上皮细胞转录本过度表达，其中富含参与紧密连接形成和纤毛组织的基因。鼻和尿PGE 2、类胰蛋白酶和抗体水平在两组之间没有差异。AERD中的IL-5抑制减少炎性类花生酸的产生并上调紧密连接相关的鼻上皮细胞转录物，这可能是由于组织肥大细胞、嗜酸性粒细胞和上皮细胞上的IL-5信号传导减少。这些对多种相关免疫细胞的直接作用有助于美泊利单抗提供的获益机制。与未接受美泊利珠单抗治疗的匹配AERD受试者相比，接受美泊利珠单抗治疗的阿司匹林加重呼吸道疾病（AERD）受试者的炎性类花生酸减少，参与紧密连接途径的鼻上皮细胞转录物上调。
Eosinophilic asthma and nasal polyposis are hallmarks of aspirin-exacerbated respiratory disease (AERD), and IL-5 inhibition has been shown to provide therapeutic benefit. However, IL-5Rα is expressed on many cells in addition to eosinophils, and the mechanisms by which IL-5 inhibition leads to clinical benefit in eosinophilic asthma and nasal polyposis are unlikely to be due exclusively to anti-eosinophil effects. We sought to identify the mechanisms by which anti-IL-5 treatment with mepolizumab improves respiratory inflammation in AERD. Clinical characteristics, circulating granulocytes, nasal scraping transcripts, eosinophilic cationic protein, tryptase, antibody levels, and urinary and nasal eicosanoid levels were measured for 18 AERD subjects on mepolizumab and were compared to 18 matched AERD subjects not on mepolizumab. Subjects on mepolizumab had significantly fewer peripheral blood eosinophils and basophils, and those cells that remained had higher surface CRTH2 expression than did those from subjects not on mepolizumab. Nasal prostaglandin (PG)F2α, PGD2 metabolites, leukotriene (LT)B4, and thromboxane levels were lower in subjects on mepolizumab, as were urinary levels of tetranor-PGD2 and LTE4. Nasal epithelial cell transcripts overexpressed among AERD subjects on mepolizumab were enriched for genes involved in tight junction formation and cilium organization. Nasal and urinary PGE2, tryptase, and antibody levels were not different between the two groups. IL-5 inhibition in AERD decreases production of inflammatory eicosanoids and upregulates tight junction-associated nasal epithelial cell transcripts, likely due to decreased IL-5 signaling on tissue mast cells, eosinophils, and epithelial cells. These direct effects on multiple relevant immune cells contributes to the mechanism of benefit afforded by mepolizumab. Subjects with aspirin-exacerbated respiratory disease (AERD) treated with mepolizumab had decreased inflammatory eicosanoids and upregulation of nasal epithelial cell transcripts involved in tight junction pathways when compared to matched subjects with AERD not treated with mepolizumab.
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影响因子：
15.3
作者：
Hsieh, F H;Lam, B K;Penrose, J F;Austen, K F;Boyce, J A
通讯作者：
Boyce, J A
影响因子：
14.2
作者：
Hulse, Kathryn E.;Norton, James E.;Suh, Lydia;Zhong, Qiu;Mahdavinia, Mahboobeh;Simon, Patrick;Kern, Robert C.;Conley, David B.;Chandra, Rakesh K.;Tan, Bruce K.;Peters, Anju T.;Grammer, Leslie C., III;Harris, Kathleen E.;Carter, Roderick G.;Kato, Atsushi;Schleimer, Robert P.
通讯作者：
Schleimer, Robert P.
DOI：
10.1016/j.jaci.2015.02.005
发表时间：
2015-06
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Laidlaw TM;Boyce JA
通讯作者：
Boyce JA
DOI：
10.1084/jem.193.2.255
发表时间：
2001-01-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hirai H;Tanaka K;Yoshie O;Ogawa K;Kenmotsu K;Takamori Y;Ichimasa M;Sugamura K;Nakamura M;Takano S;Nagata K
通讯作者：
Nagata K
DOI：
10.1056/nejmoa0808991
发表时间：
2009-03-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Haldar P;Brightling CE;Hargadon B;Gupta S;Monteiro W;Sousa A;Marshall RP;Bradding P;Green RH;Wardlaw AJ;Pavord ID
通讯作者：
Pavord ID