美泊利珠单抗或度普利尤单抗治疗重度哮喘期间2型淋巴细胞动力学的高维分析
2025/08/01
摘要
背景：尽管2型生物制剂美泊利珠单抗和度普利尤单抗临床治疗重度哮喘有效，但它们对循环淋巴细胞的影响在很大程度上尚不清楚。
目的：本研究旨在阐明美泊利珠单抗和度普利尤单抗对重度哮喘2型淋巴细胞的影响。
方法：本研究分别在接受美泊利珠单抗（n=33）或度普利尤单抗（n=7）治疗前、治疗4个月和12个月后，对40名重度哮喘患者的外周血单个核细胞进行高参数流式细胞术分析，重点分析2型淋巴细胞。此外，本研究通过单细胞RNA测序（scRNA-seq）（n=3）和2型淋巴细胞刺激实验（n=3）对美泊利珠单抗相关转录和功能变化进行探索。
结果：美泊利珠单抗可增加循环中的2型固有淋巴细胞（ILC2）、2型T辅助细胞（Th2）和2型细胞毒性细胞（Tc2）频率，使ILC2倾向于CD117低表达、CD62L高表达，Th2/Tc2细胞倾向于CD45RA-CD62L+中央记忆表型。接受度普利尤单抗治疗的患者也表现出总ILC2和CD117low-ILC2频率增加。美泊利珠单抗可降低ILC2中组织归巢受体CXCR4的表达，以及ILC2、Th2和Tc2细胞中GPR183的表达，同时增强其针对警报素产生2型细胞因子的能力。
结论：美泊利珠单抗可增加循环ILC2、Th2和Tc2细胞的频率，下调组织归巢受体的表达，但增加2型细胞因子的产生潜力。这揭示了一种潜在的新机制，即美泊利珠单抗如何通过重新引导炎症2型淋巴细胞远离气道归巢以减少气道炎症。这一发现对实现哮喘无生物制剂缓解的可能性具有重要意义。
High-Dimensional Analysis of Type 2 Lymphocyte Dynamics During Mepolizumab or Dupilumab Treatment in Severe Asthma.
Wirth L, Weigel W, Stamper CT, Kolmert J, de Souza Ferreira S, Hammer Q, Sparreman Mikus M, Theorell J, Andersson L 1st, Lantz AS, Wallén-Nielsen E, Petrén A, Wheelock CE, Bossios A, Lazarinis N, Malinovschi A, Janson C, Dahlén B, Hochdörfer T, Tibbitt CA, Dahlén SE, Yasinska V, Mjösberg J.
Abstract
BACKGROUND:
Although the type 2 biologics mepolizumab and dupilumab show clinical efficacy in severe asthma, their influence on circulating lymphocytes is largely unknown.
OBJECTIVE:
Here, we studied their impact on type 2 lymphocytes in severe asthma.
METHODS:
We performed high-parameter flow cytometry analysis of peripheral blood mononuclear cells from 40 patients with severe asthma before, and after 4 and 12 months of mepolizumab (n = 33) or dupilumab (n = 7) treatment, focusing on type 2 lymphocytes. Additionally, we performed single-cell RNA sequencing (scRNA-seq) (n = 3) and stimulation experiments of type 2 lymphocytes (n = 3) to explore transcriptional and functional changes associated with mepolizumab treatment.
RESULTS:
Mepolizumab treatment increased circulating type 2 innate lymphoid cell (ILC2), type 2 T helper (Th2) and type 2 cytotoxic (Tc2) cell frequencies, skewing ILC2 towards a CD117low signature with high CD62L expression, and Th2/Tc2 cells towards a CD45RA-CD62L+ central memory phenotype. Dupilumab-treated patients also showed increased frequencies of total ILC2 and CD117low ILC2. Mepolizumab treatment reduced the expression of tissue homing receptors CXCR4 in ILC2, and GPR183 in ILC2, Th2, and Tc2 cells while enhancing their type 2 cytokine producing capability in response to alarmins.
CONCLUSION:
Mepolizumab increases the frequencies of circulating ILC2, Th2, and Tc2 cells, with reduced tissue homing receptor expression but increased type 2 cytokine production potential. This reveals a potentially new mechanism for how mepolizumab reduces airway inflammation by re-directing trafficking of inflammatory type 2 lymphocytes away from airway-homing, with implications for the possibility of achieving biologics-free remission in asthma.
背景：尽管2型生物制剂美泊利珠单抗和度普利尤单抗临床治疗重度哮喘有效，但它们对循环淋巴细胞的影响在很大程度上尚不清楚。
目的：本研究旨在阐明美泊利珠单抗和度普利尤单抗对重度哮喘2型淋巴细胞的影响。
方法：本研究分别在接受美泊利珠单抗（n=33）或度普利尤单抗（n=7）治疗前、治疗4个月和12个月后，对40名重度哮喘患者的外周血单个核细胞进行高参数流式细胞术分析，重点分析2型淋巴细胞。此外，本研究通过单细胞RNA测序（scRNA-seq）（n=3）和2型淋巴细胞刺激实验（n=3）对美泊利珠单抗相关转录和功能变化进行探索。
结果：美泊利珠单抗可增加循环中的2型固有淋巴细胞（ILC2）、2型T辅助细胞（Th2）和2型细胞毒性细胞（Tc2）频率，使ILC2倾向于CD117低表达、CD62L高表达，Th2/Tc2细胞倾向于CD45RA-CD62L+中央记忆表型。接受度普利尤单抗治疗的患者也表现出总ILC2和CD117low-ILC2频率增加。美泊利珠单抗可降低ILC2中组织归巢受体CXCR4的表达，以及ILC2、Th2和Tc2细胞中GPR183的表达，同时增强其针对警报素产生2型细胞因子的能力。
结论：美泊利珠单抗可增加循环ILC2、Th2和Tc2细胞的频率，下调组织归巢受体的表达，但增加2型细胞因子的产生潜力。这揭示了一种潜在的新机制，即美泊利珠单抗如何通过重新引导炎症2型淋巴细胞远离气道归巢以减少气道炎症。这一发现对实现哮喘无生物制剂缓解的可能性具有重要意义。
（中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校）
（Allergy. 2025 Jun 26. doi: 10.1111/all.16633. Epub ahead of print. PMID: 40566935.）
High-Dimensional Analysis of Type 2 Lymphocyte Dynamics During Mepolizumab or Dupilumab Treatment in Severe Asthma.
Wirth L, Weigel W, Stamper CT, Kolmert J, de Souza Ferreira S, Hammer Q, Sparreman Mikus M, Theorell J, Andersson L 1st, Lantz AS, Wallén-Nielsen E, Petrén A, Wheelock CE, Bossios A, Lazarinis N, Malinovschi A, Janson C, Dahlén B, Hochdörfer T, Tibbitt CA, Dahlén SE, Yasinska V, Mjösberg J.
Abstract
BACKGROUND:
Although the type 2 biologics mepolizumab and dupilumab show clinical efficacy in severe asthma, their influence on circulating lymphocytes is largely unknown.
OBJECTIVE:
Here, we studied their impact on type 2 lymphocytes in severe asthma.
METHODS:
We performed high-parameter flow cytometry analysis of peripheral blood mononuclear cells from 40 patients with severe asthma before, and after 4 and 12 months of mepolizumab (n = 33) or dupilumab (n = 7) treatment, focusing on type 2 lymphocytes. Additionally, we performed single-cell RNA sequencing (scRNA-seq) (n = 3) and stimulation experiments of type 2 lymphocytes (n = 3) to explore transcriptional and functional changes associated with mepolizumab treatment.
RESULTS:
Mepolizumab treatment increased circulating type 2 innate lymphoid cell (ILC2), type 2 T helper (Th2) and type 2 cytotoxic (Tc2) cell frequencies, skewing ILC2 towards a CD117low signature with high CD62L expression, and Th2/Tc2 cells towards a CD45RA-CD62L+ central memory phenotype. Dupilumab-treated patients also showed increased frequencies of total ILC2 and CD117low ILC2. Mepolizumab treatment reduced the expression of tissue homing receptors CXCR4 in ILC2, and GPR183 in ILC2, Th2, and Tc2 cells while enhancing their type 2 cytokine producing capability in response to alarmins.
CONCLUSION:
Mepolizumab increases the frequencies of circulating ILC2, Th2, and Tc2 cells, with reduced tissue homing receptor expression but increased type 2 cytokine production potential. This reveals a potentially new mechanism for how mepolizumab reduces airway inflammation by re-directing trafficking of inflammatory type 2 lymphocytes away from airway-homing, with implications for the possibility of achieving biologics-free remission in asthma.
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