Depletion of major pathogenic cells in asthma by targeting CRTh2

Huang, Tao; Hazen, Meredith; Shang, Yonglei; Zhou, Meijuan; Wu, Xiumin; Yan, Donghong; Lin, Zhonghua; Solon, Margaret; Luis, Elizabeth; Ngu, Hai; Shi, Yongchang; Katewa, Arna; Choy, David F.; Ramamoorthi, Nandhini; Castellanos, Erick R.; Balázs, Mercedesz; Xu, Min; Lee, Wyne P.; Matsumoto, Marissa L.; Payandeh, Jian; Arron, Joseph R.; Hongo, Jo-Anne; Wang, Jianyong; Hötzel, Isidro; Austin, Cary D.; Reif, Karin

doi:10.1172/jci.insight.86689

Cited by 32 publications

(26 citation statements)

References 52 publications

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“…The asthma of the participants must be refractory as defined by at least two exacerbations in the previous year or an asthma control quality (ACQ) score of >1.50 while on high-dose inhaled corticosteroid (ICS) (>1,000 μg of fluticasone or equivalent daily) with or without long-acting β-agonist. Processing of the bronchial biopsy tissues for RNA isolation and gene expression microarray analyses has been described previously (29). …”

Section: Methodsmentioning

confidence: 99%

Increased Autophagy-Related 5 Gene Expression Is Associated with Collagen Expression in the Airways of Refractory Asthmatics

Poon

Choy²,

Chouiali

et al. 2017

Front. Immunol.

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BackgroundFibrosis, particularly excessive collagen deposition, presents a challenge for treating asthmatic individuals. At present, no drugs can remove or reduce excessive collagen in asthmatic airways. Hence, the identification of pathways involved in collagen deposition would help to generate therapeutic targets to interfere with the airway remodeling process. Autophagy, a cellular degradation process, has been shown to be dysregulated in various fibrotic diseases, and genetic association studies in independent human populations have identified autophagy-related 5 (ATG5) to be associated with asthma pathogenesis. Hence, the dysregulation of autophagy may contribute to fibrosis in asthmatic airways.ObjectiveThis study aimed to determine if (1) collagen deposition in asthmatic airways is associated with ATG5 expression and (2) ATG5 protein expression is associated with asthma per se and severity.MethodsGene expression of transforming growth factor beta 1, various asthma-related collagen types [collagen, type I, alpha 1; collagen, type II, alpha 1; collagen, type III, alpha 1; collagen, type V, alpha 1 (COL5A1) and collagen, type V, alpha 2], and ATG5 were measured using mRNA isolated from bronchial biopsies of refractory asthmatic subjects and assessed for pairwise associations. Protein expression of ATG5 in the airways was measured and associations were assessed for asthma per se, severity, and lung function.Main resultsIn refractory asthmatic individuals, gene expression of ATG5 was positively associated with COL5A1 in the airways. No association was detected between ATG5 protein expression and asthma per se, severity, and lung function.Conclusion and clinical relevancePositive correlation between the gene expression patterns of ATG5 and COL5A1 suggests that dysregulated autophagy may contribute to subepithelial fibrosis in the airways of refractory asthmatic individuals. This finding highlights the therapeutic potential of ATG5 in ameliorating airway remodeling in the difficult-to-treat refractory asthmatic individuals.

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Section: Methodsmentioning

confidence: 99%

Increased Autophagy-Related 5 Gene Expression Is Associated with Collagen Expression in the Airways of Refractory Asthmatics

Poon

Choy²,

Chouiali

et al. 2017

Front. Immunol.

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“…188 Neutralization of the IL-33/ST2 pathway in asthmatic patients might be predicted to have similar benefit, and its translation to patients is underway. 189 Also being explored are CRTH2 antagonists 190 and CRTH2 depleting mAbs, 191 which target memory T H 2 cells, as well as CRTH2 + innate immune cells (eosinophils, basophils, and ILC2s) that have homed to the lungs.…”

Section: Future Directions and Clinical Implicationsmentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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“…Compounds have entered clinical trials. Notably, Fevipiprant treatment of patients on inhaled corticosteroids improved Forced Expiratory Volume and reduced sputum eosinophilia [189][190][191][192] Anti-huCRTH2 antibody Pre-clinical humanized anti-huCRTH2 antibody causes depletion of CRTH2-expressing cells 193 Leukotriene pathway Montelukast and Zafirlukast are cysteinyl leukotriene receptor antagonists ILC2 expression of type-2 cytokines is partially inhibited by Montelukast in vitro 182,194 Arginase 2(S)-amino-6-boronohexonic acid (ABH) or S-(2-boronoethyl)-L-cysteine (BEC)…”

Section: Introductionmentioning

confidence: 99%

Pulmonary group 2 innate lymphoid cells: surprises and challenges

et al. 2019

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Group 2 innate lymphoid cells (ILC2s) are a recently described subset of innate lymphocytes with important immune and homeostatic functions at multiple tissue sites, especially the lung. These cells expand locally after birth and during postnatal lung maturation and are present in the lung and other peripheral organs. They are modified by a variety of processes and mediate inflammatory responses to respiratory pathogens, inhaled allergens and noxious particles. Here, we review the emerging roles of ILC2s in pulmonary homeostasis and discuss recent and surprising advances in our understanding of how hormones, age, neurotransmitters, environmental challenges, and infection influence ILC2s. We also review how these responses may underpin the development, progression and severity of pulmonary inflammation and chronic lung diseases and highlight some of the remaining challenges for ILC2 biology.Mucosal Immunology (2019) 12:299-311; https://doi.

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Depletion of major pathogenic cells in asthma by targeting CRTh2

Cited by 32 publications

References 52 publications

Increased Autophagy-Related 5 Gene Expression Is Associated with Collagen Expression in the Airways of Refractory Asthmatics

Increased Autophagy-Related 5 Gene Expression Is Associated with Collagen Expression in the Airways of Refractory Asthmatics

Pathogenic CD4 + T cells in patients with asthma

Pulmonary group 2 innate lymphoid cells: surprises and challenges

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