Selective Targeting of Tumour Necrosis Factor Receptor 1 Induces Stable Protection from Crohn's-Like Ileitis in TNFΔARE Mice

Overview

Journal J Crohns Colitis

Publisher Oxford University Press

Date 2021 Dec 11

PMID 34893805

Authors

Rajrupa Chakraborty

Mia R Maltz

Diana Del Castillo

Purvi N Tandel

Nathalie Messih

Martha Anguiano

David D Lo

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Crohn's disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. Current interventions using anti-tumour necrosis factor [anti-TNF] biologics show long-term benefit in only half of patients. This study focused on the role of the TNF receptor 1 [TNFR1] in pathogenesis in a TNF-driven model of ileitis.

Methods: We studied TNFΔAU-rich element [ARE]/+ [TNFdARE] mice, which develop progressive ileitis similar to Crohn's ileitis. Histopathological analysis and gene expression profiling were used to characterize disease progression from 5 to 16 weeks. Mice with TNFR1 hemizygosity [TNFdARE/R1het] allowed us to assess gene dosage effects. Transcriptional profiling established inflection points in disease progression; inflammatory gene expression increased at 8 weeks with a plateau by 10 weeks, so these were selected as endpoints of treatment using the TNF biologic infliximab and the TNFR1-specific XPro1595. Differences in recruitment of cells in the lamina propria were assessed using flow cytometry.

Results: TNFdARE/R1het mice displayed stable long-term protection from disease, associated with decreased recruitment of CD11bhiF4/80lo monocytes and CD11bhiLy6Ghi neutrophils, suggesting an important role of TNFR1 signalling in pathogenesis, and indicating potential benefit from TNFR1-specific intervention. Treatment with infliximab and XPro1595 both showed a similar impact on disease in TNFdARE mice. Importantly, these beneficial effects were greatly surpassed by hemizygosity at the TNFR1 locus.

Conclusions: Treatment with either infliximab or XPro1595 produced moderate protection from ileitis in TNFdARE mice. However, hemizygosity at the TNFR1 locus in TNFdARE mice showed far better protection, implicating TNFR1 signalling as a key mediator of TNF-driven disease.

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