Collaborative cross strain CC011/UncJ as a novel mouse model of T2-high, severe asthma.
Collaborative cross strain CC011/UncJ as a novel mouse model of T2-high, severe asthma.
复制标题
DOI：
10.1186/s12931-023-02453-y
复制
发表时间：
2023-06-09
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
--
作者：
在哮喘患者中，临床表现和潜在的病理生理机制存在显著的异质性，导致对多种疾病内在型的认识（例如，T2-高与T2-低）。这种异质性延伸到严重的哮喘患者，即使使用高剂量皮质类固醇治疗和其他疗法，他们也可能难以控制症状。然而，有有限的小鼠模型可用于模拟严重哮喘内源型谱。我们试图确定一个新的小鼠模型的严重哮喘，首先检查慢性过敏原暴露的菌株之间的合作交叉（CC）小鼠遗传学参考人群，其中包含更大的遗传多样性比其他近交系的面板先前用于模型的哮喘。将来自5个CC品系和常用的经典近交系BALB/cJ的小鼠长期暴露于屋尘螨（HDM）变应原5周，然后测量气道炎症。CC菌株CC 011/UncJ（CC 011）对HDM表现出极端反应，包括高水平的气道嗜酸性粒细胞增多、肺阻力升高和广泛的气道壁重塑，甚至在研究完成前约50%的小鼠死亡。与BALB/cJ小鼠相比，CC 011小鼠具有更强的Th 2介导的气道反应，表现为在抗原回忆试验期间显著升高的总IgE和HDM特异性IgE以及增加的Th 2细胞因子，但不增强ILC 2活化。CC 011小鼠的气道嗜酸性粒细胞增多完全依赖于CD 4 + T细胞。值得注意的是，我们还发现CC 011小鼠的气道嗜酸性粒细胞增多症对地塞米松类固醇治疗具有抗性。因此，CC 011品系提供了一种由可能通过CD 4 + T细胞起作用的天然遗传变异驱动的T2高、严重哮喘的新小鼠模型。未来的研究旨在确定这种表型的遗传基础，将为严重哮喘的潜在机制提供新的见解。在线版本包含补充材料，可通过10.1186/s12931-023-02453-y获得。
Among asthmatics, there is significant heterogeneity in the clinical presentation and underlying pathophysiological mechanisms, leading to the recognition of multiple disease endotypes (e.g., T2-high vs. T2-low). This heterogeneity extends to severe asthmatics, who may struggle to control symptoms even with high-dose corticosteroid treatment and other therapies. However, there are limited mouse models available to model the spectrum of severe asthma endotypes. We sought to identify a new mouse model of severe asthma by first examining responses to chronic allergen exposure among strains from the Collaborative Cross (CC) mouse genetics reference population, which contains greater genetic diversity than other inbred strain panels previously used for models of asthma. Mice from five CC strains and the often-used classical inbred strain BALB/cJ were chronically exposed to house dust mite (HDM) allergen for five weeks followed by measurements of airway inflammation. CC strain CC011/UncJ (CC011) exhibited extreme responses to HDM including high levels of airway eosinophilia, elevated lung resistance, and extensive airway wall remodeling, and even fatalities among ~ 50% of mice prior to study completion. Compared to BALB/cJ mice, CC011 mice had stronger Th2-mediated airway responses demonstrated by significantly elevated total and HDM-specific IgE and increased Th2 cytokines during tests of antigen recall, but not enhanced ILC2 activation. Airway eosinophilia in CC011 mice was completely dependent upon CD4+ T-cells. Notably, we also found that airway eosinophilia in CC011 mice was resistant to dexamethasone steroid treatment. Thus, the CC011 strain provides a new mouse model of T2-high, severe asthma driven by natural genetic variation likely acting through CD4+ T-cells. Future studies aimed at determining the genetic basis of this phenotype will provide new insights into mechanisms underlying severe asthma. The online version contains supplementary material available at 10.1186/s12931-023-02453-y.
登录
查看更多内容
DOI：
10.1016/j.jaci.2021.03.015
发表时间：
2021-05
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Bartemes KR;Kita H
通讯作者：
Kita H
将哮喘的小鼠模型与人类疾病的内型统一。
DOI：
10.1111/resp.12315
发表时间：
2014-08
期刊：
Respirology (Carlton, Vic.)
影响因子：
--
作者：
Martin RA;Hodgkins SR;Dixon AE;Poynter ME
通讯作者：
Poynter ME
DOI：
10.1016/j.jaci.2017.12.1009
发表时间：
2019-01
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Peters MC;Kerr S;Dunican EM;Woodruff PG;Fajt ML;Levy BD;Israel E;Phillips BR;Mauger DT;Comhair SA;Erzurum SC;Johansson MW;Jarjour NN;Coverstone AM;Castro M;Hastie AT;Bleecker ER;Wenzel SE;Fahy JV;National Heart, Lung and Blood Institute Severe Asthma Research Program 3
通讯作者：
National Heart, Lung and Blood Institute Severe Asthma Research Program 3
影响因子：
4.6
作者：
Mato N;Hirahara K;Ichikawa T;Kumagai J;Nakayama M;Yamasawa H;Bando M;Hagiwara K;Sugiyama Y;Nakayama T
通讯作者：
Nakayama T
影响因子：
14.2
作者：
Orgel, Kelly;Smeekens, Johanna M.;Kulis, Michael D.
通讯作者：
Kulis, Michael D.