人PD-1激动剂通过重编程T细胞减轻嗜中性粒细胞性哮喘
2022/09/20
摘要
背景：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。需要新的疗法来处理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细胞效应器功能免疫应答的关键稳态调节剂。
目的：我们的目的是在气道高反应性（AHR）小鼠模型中研究PD-1在调节急性中性粒细胞炎症中的作用。
方法：用屋尘螨诱导和比较野生型和PD-1基因敲除小鼠中性粒细胞AHR。然后在人源化小鼠模型中测试人PD-1激动剂的治疗潜力，其中PD-1胞外结构域完全人源化。单细胞RNA测序和流式细胞术主要用于研究分子和细胞机制。
结果：在我们的炎症模型中，PD-1在肺T细胞上高度诱导。PD-1缺乏与中性粒细胞AHR增加和炎症细胞向肺的大量募集有关。在人源化PD-1小鼠模型中，PD-1激动剂抑制AHR，减少中性粒细胞募集，并调节细胞因子产生。从机制上讲，我们在转录和蛋白质水平上证明了PD-1激动剂的抑制作用与肺效应T细胞的重编程有关，该细胞的数量和活化减少。
结论：在临床前人源化小鼠模型中，PD-1激动剂可有效抑制中性粒细胞AHR和肺部炎症。
Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells
Doumet Georges Helou, Christine Quach, Marshall Fung, Jacob D Painter, Benjamin P Hurrell, Yong-Hwee Eddie Loh, Emily Howard, Pedram Shafiei-Jahani, Pejman Soroosh, Arlene H Sharpe, Omid Akbari
Abstract
Background：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.
Objective：Our aim here was to investigate the role of PD-1 in the regulation of acute neutrophilic inflammation in a murine model of airway hyperreactivity (AHR).
Methods：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.
Results：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.
Conclusion：PD-1 agonist treatment is efficient in dampening neutrophilic AHR and lung inflammation in a preclinical humanized mouse model.
背景：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。需要新的疗法来处理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细胞效应器功能免疫应答的关键稳态调节剂。
目的：我们的目的是在气道高反应性（AHR）小鼠模型中研究PD-1在调节急性中性粒细胞炎症中的作用。
方法：用屋尘螨诱导和比较野生型和PD-1基因敲除小鼠中性粒细胞AHR。然后在人源化小鼠模型中测试人PD-1激动剂的治疗潜力，其中PD-1胞外结构域完全人源化。单细胞RNA测序和流式细胞术主要用于研究分子和细胞机制。
结果：在我们的炎症模型中，PD-1在肺T细胞上高度诱导。PD-1缺乏与中性粒细胞AHR增加和炎症细胞向肺的大量募集有关。在人源化PD-1小鼠模型中，PD-1激动剂抑制AHR，减少中性粒细胞募集，并调节细胞因子产生。从机制上讲，我们在转录和蛋白质水平上证明了PD-1激动剂的抑制作用与肺效应T细胞的重编程有关，该细胞的数量和活化减少。
结论：在临床前人源化小鼠模型中，PD-1激动剂可有效抑制中性粒细胞AHR和肺部炎症。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2022 Aug 10;S0091-6749(22)01049-1. doi: 10.1016/j.jaci.2022.07.022.)
(J Allergy Clin Immunol. 2022 Aug 10;S0091-6749(22)01049-1. doi: 10.1016/j.jaci.2022.07.022.)
Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells
Doumet Georges Helou, Christine Quach, Marshall Fung, Jacob D Painter, Benjamin P Hurrell, Yong-Hwee Eddie Loh, Emily Howard, Pedram Shafiei-Jahani, Pejman Soroosh, Arlene H Sharpe, Omid Akbari
Abstract
Background：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.
Objective：Our aim here was to investigate the role of PD-1 in the regulation of acute neutrophilic inflammation in a murine model of airway hyperreactivity (AHR).
Methods：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.
Results：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.
Conclusion：PD-1 agonist treatment is efficient in dampening neutrophilic AHR and lung inflammation in a preclinical humanized mouse model.
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