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1238
UTILIZING A NOVEL PRE-CLINICAL MOUSE MODEL OF EARLY ONSET EOSINOPHILIC ESOPHAGITIS THROUGH CONDITIONAL IL-13 OVEREXPRESSION TO ILLUMINATE THE ROLE OF TENASCIN-C IN PEDIATRIC EOSINOPHILIC ESOPHAGITIS
Date
May 9, 2023
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Background: Eosinophilic Esophagitis (EoE) is one of the most predominant causes of chronic esophageal symptoms in children. Pathological changes of the esophageal epithelium in EoE are characterized by basal cell hyperplasia (BCH), infiltration of eosinophils and elevated levels of cytokines (e.g. IL-4 and IL-13). Our knowledge of EoE pathogenesis has mostly relied on adult animal models, despite unique clinical phenotypes of pediatric EoE. Accumulation of the extracellular matrix protein tenascin-C (TNC) is associated with asthma; however, its role in EoE pathogenesis has not been investigated. Using proteomics, our preliminary data show that TNC is dramatically increased in IL-13 treated human esophageal basal cells (EPC2 cells). We hypothesize that IL-13 induced pediatric EoE progression is dependent on TNC which modulates BCH. Methods: We adapted our previously established transgenic mouse model to generate Krt5-rtTA; tetO-IL13 mice pups. To examine the role of TNC deletion in our pre-weaning mouse model of pediatric EoE, we generated Krt5-rtTA; tetO-IL-13; TNC-/- pups to determine the effects on the development of EoE. We also investigated the effect of TNC knockdown in IL-13 treated EPC2 cells using siRNA. Furthermore, we examined human esophageal biopsies from EoE patients and healthy controls to evaluate TNC and IL-13 levels, BCH and esophageal eosinophilia and their correlation with EoE disease stage. Results: IL-13 overexpression was detected in hyperplastic basal cells of Krt5-rtTA; tetO-IL13 transgenic pre-weaning mice upon doxycycline water feeding. Keratin 5 (Krt-5), TNC and major basic protein (MBP) immunostaining confirmed TNC expression in hyperproliferative basal cells in addition to eosinophils in the esophageal epithelium of these pre-weaning mice. These mice weighed less than controls; resembling a failure to thrive phenotype as seen in human infants with EoE as well as skin lesions similar to atopic dermatitis. Deletion of TNC in the transgenic pre-weaning mouse esophagus reduces the thickness of basal cell layers (p63+ Krt5+), proliferation (p63+ Ki67+) and differentiation (Krt13+) of basal cells. TNC knockdown reduces the number of proliferating (p63+ Ki67+) EPC2 cells. Consistently, TNC expression is increased in esophageal biopsy specimens from EoE patients as compared to healthy controls. Conclusions:For the first time, we demonstrate that our novel transgenic pre-weaning EoE mouse model shows that TNC is not only critical but also plays a conserved role in epithelial remodeling in the early stages of EoE pathogenesis. Future directions include whether the mechanism involving TNC may be also used in other allergen associated diseases including atopic dermatitis. Keywords: eosinophilic esophagitis, IL-13, basal cell hyperplasia, Tenascin-C, pediatric mouse model
Switching from originator to biosimilar infliximab (IFX) is effective and safe. However, data on multiple switching are scarce. The Edinburgh IBD unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021)…
Switching from originator to biosimilar infliximab (IFX) is effective and safe. However, data on multiple switching are scarce. The Edinburgh IBD unit has undertaken three switch programmes: (1) Remicade to CT-P13 (2016), (2) CT-P13 to SB2 (2020), and (3) SB2 to CT-P13 (2021)…