重组多聚体犬变应原可防止以强烈TH2和TH17细胞反应为标志的哮喘模型的气道高反应性
2022/06/17
摘要
发达国家约10%的人口对狗过敏。用狗过敏原提取物对过敏患者进行免疫治疗的疗效有限。在此，我们建立了狗过敏的小鼠模型，并测试了含有Can f1、f2、f4和f6的重组多聚体蛋白在防止狗提取物炎症反应方面的功效。反复吸入狗提取物可诱导Th2细胞、嗜酸性粒细胞和杯状细胞浸润气道，使人联想起屋尘螨（HDM）哮喘模型。狗提取物还可诱导强烈的气道高反应性，并促进TH17细胞反应，这与气道的高中性粒细胞浸润有关。气道中辅助性T细胞的scRNA序列分析确定了几个独特的簇，其中TH17细胞以包括IL-17RE在内的受体的表达为特征。对T细胞受体的分析表明，TH17、TH2和抑制性Treg细胞之间共享的克隆频率较高，表明这些亚群具有共同的分化轨迹。重要的是，在此模型中，在致敏前舌下给予多聚Can f 1-2-4-6蛋白可降低气道高反应性和2型介导的炎症。
A recombinant multimeric dog allergen prevents airway hyperresponsiveness in a model of asthma marked by vigorous T H 2 and T H 17 cell responses
Julian M Stark, Jielu Liu, Christopher A Tibbitt, Murray Christian, Junjie Ma, Anna Wintersand, Josefine Dunst, Taras Kreslavsky, Ben Murrell, Mikael Adner, Hans Grönlund, Guro Gafvelin, Jonathan M Coquet
Abstract
Allergy to dogs affects around ten percent of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit. Herein, we established a mouse model of dog allergy and tested the efficacy of a recombinant multimeric protein containing Can f 1, f 2, f 4 and f 6 in preventing inflammatory responses to dog extracts. Repeated inhalation of dog extracts induced infiltration of the airways by TH 2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. Dog extracts also induced robust airway hyperresponsiveness and promoted TH 17 cell responses, which was associated with a high neutrophilic infiltration of the airways. scRNA-Seq analysis of T helper cells in the airways identified several unique clusters with TH 17 cells being hallmarked by the expression of receptors including IL-17RE. Analysis of T cell receptors depicted a high frequency of clones that were shared between TH 17, TH 2 and suppressive Treg cells, indicative of a common differentiation trajectory for these subsets. Importantly, sublingual administration of multimeric Can f 1-2-4-6 protein prior to sensitisation reduced airway hyperresponsiveness and type 2-mediated inflammation in this model.
发达国家约10%的人口对狗过敏。用狗过敏原提取物对过敏患者进行免疫治疗的疗效有限。在此，我们建立了狗过敏的小鼠模型，并测试了含有Can f1、f2、f4和f6的重组多聚体蛋白在防止狗提取物炎症反应方面的功效。反复吸入狗提取物可诱导Th2细胞、嗜酸性粒细胞和杯状细胞浸润气道，使人联想起屋尘螨（HDM）哮喘模型。狗提取物还可诱导强烈的气道高反应性，并促进TH17细胞反应，这与气道的高中性粒细胞浸润有关。气道中辅助性T细胞的scRNA序列分析确定了几个独特的簇，其中TH17细胞以包括IL-17RE在内的受体的表达为特征。对T细胞受体的分析表明，TH17、TH2和抑制性Treg细胞之间共享的克隆频率较高，表明这些亚群具有共同的分化轨迹。重要的是，在此模型中，在致敏前舌下给予多聚Can f 1-2-4-6蛋白可降低气道高反应性和2型介导的炎症。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Allergy.2022 Jun 3.doi: 10.1111/all.15399. )
(Allergy.2022 Jun 3.doi: 10.1111/all.15399. )
A recombinant multimeric dog allergen prevents airway hyperresponsiveness in a model of asthma marked by vigorous T H 2 and T H 17 cell responses
Julian M Stark, Jielu Liu, Christopher A Tibbitt, Murray Christian, Junjie Ma, Anna Wintersand, Josefine Dunst, Taras Kreslavsky, Ben Murrell, Mikael Adner, Hans Grönlund, Guro Gafvelin, Jonathan M Coquet
Abstract
Allergy to dogs affects around ten percent of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit. Herein, we established a mouse model of dog allergy and tested the efficacy of a recombinant multimeric protein containing Can f 1, f 2, f 4 and f 6 in preventing inflammatory responses to dog extracts. Repeated inhalation of dog extracts induced infiltration of the airways by TH 2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. Dog extracts also induced robust airway hyperresponsiveness and promoted TH 17 cell responses, which was associated with a high neutrophilic infiltration of the airways. scRNA-Seq analysis of T helper cells in the airways identified several unique clusters with TH 17 cells being hallmarked by the expression of receptors including IL-17RE. Analysis of T cell receptors depicted a high frequency of clones that were shared between TH 17, TH 2 and suppressive Treg cells, indicative of a common differentiation trajectory for these subsets. Importantly, sublingual administration of multimeric Can f 1-2-4-6 protein prior to sensitisation reduced airway hyperresponsiveness and type 2-mediated inflammation in this model.
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大鼠肺和鼻上皮的过敏性炎症受组织特异性miRNA表达的调控
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嗜酸性粒细胞介导的抑制和抗IL-5增强哮喘患者浆细胞样树突状细胞干扰素反应
