An anti–IL-13 antibody reverses epithelial-mesenchymal transition biomarkers in eosinophilic esophagitis: Phase 2 trial results

Gann, Peter H.; Deaton, Ryan; McMahon, Nathan P.; Collins, Margaret H.; Dellon, Evan S.; Hirano, Ikuo; Hua, Steven; Rodriguez, Cristian; Harris, Sarah

doi:10.1016/j.jaci.2020.03.045

Cited by 37 publications

(20 citation statements)

References 36 publications

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“…Indeed, biologics directed against IgE (omalizumab) and eosinophils (anti-IL-5 reslizumab and mepolizumab) have been shown to control asthma in patients with allergic sensitisation and an eosinophilic endotype ( 211 , 212 ) but have not been proven to be helpful in EoE ( 213 , 214 ). On the other hand, antibodies with broader Th2 inhibition like antiIL-4/IL-13 or anti-IL-13 seem to be more effective in controlling EoE ( 215 , 216 ). Due to its genetic predisposition, studies, particularly those involving sibling and twins, have helped to understand how such inflammation develops in EoE ( 217 ).…”

Section: What Can We Learn From Eosinophilic Oesophagitis (Eoe) and The Importance Of The Epithelium In Driving Atopic Chronic Inflammatimentioning

confidence: 99%

Viral Induced Effects on a Vulnerable Epithelium; Lessons Learned From Paediatric Asthma and Eosinophilic Oesophagitis

et al. 2021

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The epithelium is integral to the protection of many different biological systems and for the maintenance of biochemical homeostasis. Emerging evidence suggests that particular children have epithelial vulnerabilities leading to dysregulated barrier function and integrity, that resultantly contributes to disease pathogenesis. These epithelial vulnerabilities likely develop in utero or in early life due to various genetic, epigenetic and environmental factors. Although various epithelia are uniquely structured with specific function, prevalent allergic-type epithelial diseases in children potentially have common or parallel disease processes. These include inflammation and immune response dysregulation stemming from atypical epithelial barrier function and integrity. Two diseases where aetiology and pathogenesis are potentially linked to epithelial vulnerabilities include Paediatric Asthma and Eosinophilic Oesophagitis (EoE). For example, rhinovirus C (RV-C) is a known risk factor for paediatric asthma development and is known to disrupt respiratory epithelial barrier function causing acute inflammation. In addition, EoE, a prevalent atopic condition of the oesophageal epithelium, is characterised by similar innate immune and epithelial responses to viral injury. This review examines the current literature and identifies the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation, drawing from knowledge generated in acute wheezing illness, paediatric asthma and EoE. Besides highlighting the importance of epithelial structure and barrier function in allergic disease pathogenesis regardless of specific epithelial sub-types, this review focuses on the importance of examining other parallel allergic-type disease processes that may uncover commonalities driving disease pathogenesis. This in turn may be beneficial in the development of common therapeutics for current clinical management and disease prevention in the future.

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Section: What Can We Learn From Eosinophilic Oesophagitis (Eoe) and The Importance Of The Epithelium In Driving Atopic Chronic Inflammatimentioning

confidence: 99%

Viral Induced Effects on a Vulnerable Epithelium; Lessons Learned From Paediatric Asthma and Eosinophilic Oesophagitis

et al. 2021

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“…Convincing evidence suggests that EMT is involved in promoting invasion and metastasis in pancreatic cancer [ 28 ]. In other visceral malignancies, IL-13 stimulation was associated with increased EMT [ 45 , 46 ]. Similarly, in our results, the exogenous stimulation resulted in increased cell migration.…”

Section: Discussionmentioning

confidence: 99%

Loss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer

Shi

Shen

Kang

et al. 2022

IJMS

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In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer.

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“…There are few studies on the expression of Hb in esophageal epithelial cells, although the expression of Hb in non‐erythroid cells such as alveolar epithelial cells and renal mesangial cells has been reported 13,14 . Epithelial–mesenchymal transition (EMT) is considered to contribute to esophageal remodeling and reverses with treatment in EoE 15,16 . EMT describes a series of events in which epithelia lose many epithelial characteristics, including polarity and tight junctions, and acquire properties of mesenchymal cells, including motility and loose cell adhesion 17 .…”

Section: Discussionmentioning

confidence: 99%

Beige mucosa observable under narrow‐band imaging indicates the active sites of eosinophilic esophagitis

Ayaki

Manabe

Tomida³

et al. 2022

J of Gastro and Hepatol

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Background and Aim The majority of patients with eosinophilic esophagitis (EoE) are likely to have observable features under narrow‐band imaging, namely beige mucosa. However, the histological features and clinical implications of beige mucosa have not been investigated. The aim of this study was to determine whether beige mucosa could serve as an endoscopic marker for predicting active inflammatory sites of EoE. Methods We retrospectively analyzed both the narrow‐band images and biopsied specimens of 77 esophageal lesions from 35 consecutive patients with EoE. We divided these specimens into two groups: target biopsied specimens from beige mucosa (beige group) and specimens biopsied from non‐beige mucosa (non‐beige group). The number of eosinophils per high‐powered field, thickness of the superficial differentiated cell layer, and depth of the hemoglobin component from the surface layer were compared between the two groups. Results Forty‐four out of the 45 specimens were diagnosed as histological active lesions in the beige group. The sensitivity, specificity, and overall accuracy of beige mucosa in predicting EoE activity were 97.8%, 96.9%, and 97.8%, respectively. Compared with the non‐beige group, specimens in the beige group had a significantly thinner superficial differentiated cell layer. Conclusions Beige mucosa is associated with thinning of the normal superficial differentiated cell layer, and these histological changes in the active inflammatory sites of EoE could be recognized endoscopically as color differences. Beige mucosa may serve as an endoscopic indicator for predicting the histological activity of EoE.

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An anti–IL-13 antibody reverses epithelial-mesenchymal transition biomarkers in eosinophilic esophagitis: Phase 2 trial results

Abstract: This study was sponsored by Celgene. Support for third-party writing assistance for this article was provided by CodonMedical (an Ashfield Company that is part of UDG Healthcare and Peloton Advantage, an OPEN Health Company) and was funded by Celgene Corporation.

Cited by 37 publications

References 36 publications

Viral Induced Effects on a Vulnerable Epithelium; Lessons Learned From Paediatric Asthma and Eosinophilic Oesophagitis

Viral Induced Effects on a Vulnerable Epithelium; Lessons Learned From Paediatric Asthma and Eosinophilic Oesophagitis

Loss of Interleukin-13-Receptor-Alpha-1 Induces Apoptosis and Promotes EMT in Pancreatic Cancer

Beige mucosa observable under narrow‐band imaging indicates the active sites of eosinophilic esophagitis

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