Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
USC Libraries Bioinformatics Service, University of Southern California, Los Angeles, Calif.
J Allergy Clin Immunol. 2023 Feb;151(2):526-538.e8. doi: 10.1016/j.jaci.2022.07.022. Epub 2022 Aug 11.
Neutrophilic asthma is associated with disease severity and corticosteroid insensitivity. Novel therapies are required to manage this life-threatening asthma phenotype. Programmed cell death protein-1 (PD-1) is a key homeostatic modulator of the immune response for T-cell effector functions.
We sought to investigate the role of PD-1 in the regulation of acute neutrophilic inflammation in a murine model of airway hyperreactivity (AHR).
House dust mite was used to induce and compare neutrophilic AHR in wild-type and PD-1 knockout mice. Then, the therapeutic potential of a human PD-1 agonist was tested in a humanized mouse model in which the PD-1 extracellular domain is entirely humanized. Single-cell RNA sequencing and flow cytometry were mainly used to investigate molecular and cellular mechanisms.
PD-1 was highly induced on pulmonary T cells in our inflammatory model. PD-1 deficiency was associated with an increased neutrophilic AHR and high recruitment of inflammatory cells to the lungs. Consistently, PD-1 agonist treatment dampened AHR, decreased neutrophil recruitment, and modulated cytokine production in a humanized PD-1 mouse model. Mechanistically, we demonstrated at the transcriptional and protein levels that the inhibitory effect of PD-1 agonist is associated with the reprogramming of pulmonary effector T cells that showed decreased number and activation.
PD-1 agonist treatment is efficient in dampening neutrophilic AHR and lung inflammation in a preclinical humanized mouse model.
中性粒细胞性哮喘与疾病严重程度和皮质类固醇不敏感有关。需要新的疗法来治疗这种危及生命的哮喘表型。程序性细胞死亡蛋白-1（PD-1）是 T 细胞效应功能免疫反应的关键稳态调节剂。
我们旨在研究 PD-1 在气道高反应性（AHR）小鼠模型中调节急性中性粒细胞炎症中的作用。
使用屋尘螨诱导并比较野生型和 PD-1 敲除小鼠的中性粒细胞性 AHR。然后，在人源化小鼠模型中测试了一种人 PD-1 激动剂的治疗潜力，其中 PD-1 细胞外结构域完全人源化。主要使用单细胞 RNA 测序和流式细胞术来研究分子和细胞机制。
在我们的炎症模型中，PD-1 在肺部 T 细胞上高度诱导。PD-1 缺乏与中性粒细胞性 AHR 增加和炎症细胞向肺部的高募集有关。一致地，PD-1 激动剂治疗可减轻 AHR、减少中性粒细胞募集，并调节人源化 PD-1 小鼠模型中的细胞因子产生。在转录和蛋白质水平上，我们证明了 PD-1 激动剂的抑制作用与肺部效应 T 细胞的重编程有关，这些细胞的数量和激活减少。
PD-1 激动剂治疗在一种临床前人源化小鼠模型中可有效抑制中性粒细胞性 AHR 和肺部炎症。
