Background and Aims: Crohn’s disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. While current therapeutic interventions using anti-TNF biologics show long-term benefit in up to half of the patients, broadly effective approaches are still needed. This study focused on the role of the TNF receptor 1 (TNFR1) in disease pathogenesis in a TNF-driven model of ileitis, and the relative benefits of global TNF blockade versus TNFR1-targeted modulation.

Methods: We studied genetically engineered TNF^{DAU-rich element (ARE)/+} (TNFdARE) mice, which develop progressive ileitis, with similarities to Crohn’s ileitis in humans. Histopathological analysis and gene expression profiling was used to characterize the progression of disease in 5 to 16-week old TNFdARE mice. In addition, we studied mice with TNFR1 hemizygosity (TNFdARE/R1het) to assess gene dosage effects on disease pathogenesis. Transcriptional profiling, at various ages, established inflection points in disease progression; upregulation in inflammatory gene expression at 8 weeks and a plateau in activity after 10 weeks, were used to select the start and endpoints, respectively, of treatment using global TNF blockade biologic Infliximab and the TNFR1-specific drug XPro1595. Differences in the recruitment of immune cells in the small intestinal lamina propria of TNFdARE and TNFdARE/R1het mice were assessed using flow cytometry.

Results: TNFdARE/R1het mice proved to have a surprisingly stable long term protection from disease, which was associated with decreased recruitment of CD11b^hiF4/80^lo monocytes and CD11b^hiLy6G^hi neutrophils in the small intestinal lamina propria, suggesting an important role of TNFR1 signaling in disease pathogenesis, and indicating potential benefit from TNFR1-specific intervention. Treatment with Infliximab and XPro1595 both showed a significant reduction of disease in TNFdARE mice, with a similar degree of benefit. Importantly, these beneficial effects were greatly surpassed by hemizygosity at the TNFR1 locus.

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