Wirth Lorenz, Weigel Whitney, Stamper Christopher T, Kolmert Johan, de Souza Ferreira Sabrina, Hammer Quirin, Sparreman Mikus Maria, Theorell Jakob, Andersson Lars, Lantz Ann-Sofie, Wallén-Nielsen Eva, Petrén Anne, Wheelock Craig E, Bossios Apostolos, Lazarinis Nikolaos, Malinovschi Andrei, Janson Christer, Dahlén Barbro, Hochdörfer Thomas, Tibbitt Christopher Andrew, Dahlén Sven-Erik, Yasinska Valentyna, Mjösberg Jenny
Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Mechanistic Biology and Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
Allergy. 2025 Jun 26. doi: 10.1111/all.16633.
Although the type 2 biologics mepolizumab and dupilumab show clinical efficacy in severe asthma, their influence on circulating lymphocytes is largely unknown. Here, we studied their impact on type 2 lymphocytes in severe asthma.
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.
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 CD117 signature with high CD62L expression, and Th2/Tc2 cells towards a CD45RACD62L central memory phenotype. Dupilumab-treated patients also showed increased frequencies of total ILC2 and CD117 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.
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.
尽管第二代生物制剂美泊利珠单抗和度普利尤单抗在重度哮喘中显示出临床疗效，但其对循环淋巴细胞的影响在很大程度上尚不清楚。在此，我们研究了它们对重度哮喘中2型淋巴细胞的影响。
我们对40例重度哮喘患者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个月后外周血单个核细胞进行了高参数流式细胞术分析，重点关注2型淋巴细胞。此外，我们进行了单细胞RNA测序（scRNA-seq）（n = 3）和2型淋巴细胞刺激实验（n = 3），以探索与美泊利珠单抗治疗相关的转录和功能变化。
美泊利珠单抗治疗增加了循环2型固有淋巴细胞（ILC2）、2型辅助性T细胞（Th2）和2型细胞毒性T细胞（Tc2）的频率，使ILC2向具有高CD62L表达的CD117特征偏移，使Th2/Tc2细胞向CD45RACD62L中央记忆表型偏移。接受度普利尤单抗治疗的患者也显示出总ILC2和CD117 ILC2频率增加。美泊利珠单抗治疗降低了ILC2中组织归巢受体CXCR4以及ILC2、Th2和Tc2细胞中GPR183的表达，同时增强了它们对警报素产生2型细胞因子的能力。
美泊利珠单抗增加了循环ILC2、Th2和Tc2细胞的频率，降低了组织归巢受体表达，但增加了2型细胞因子产生潜力。这揭示了美泊利珠单抗通过将炎症性2型淋巴细胞的归巢从气道重新导向来减轻气道炎症的潜在新机制，这对哮喘实现无生物制剂缓解的可能性具有重要意义。
