High Smad7 in the early post-operative recurrence of Crohn\u2019s disease

Giovanni Monteleone,Sara Casella,Giampiero Palmieri,Emma Calabrese,Davide Di Fusco,Elena De Cristofaro,Francesca Zorzi,Livia Biancone

doi:10.1186/s12967-020-02558-8

Giovanni Monteleone, Sara Casella + Show 6 more

Open Access

https://doi.org/10.1186/s12967-020-02558-8

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Abstract

BackgroundIn Crohn’s disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this study was to assess whether Smad7 over-expression occurs in the early and/or late phases of CD.MethodsMucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with or without (early CD) post-operative endoscopic recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (late CD). Smad7 was examined by immunohistochemistry and cytokine expression was analysed by flow-cytometry.ResultsBefore the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of Smad7-expressing cells in both the epithelial and lamina propria compartments. Transition from this stage to endoscopic recurrence was marked by persistence of high number of Smad7-positive cells, which reduced significantly in the late stages of the disease, where Smad7 expression remained, however, greater than that seen in normal controls. In samples with early lesions, Smad7 expression positively correlated with the number of interferon-γ-secreting cells.ConclusionsSmad7 induction is an early event in the inflammatory sequence occurring in CD, thus suggesting that knockdown of Smad7 can help prevent post-operative recurrence.

Highlights

In Crohn’s disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine Transforming growth factor (TGF-β1)
[13] Such a defect is secondary to elevated levels of Smad7, an intracellular protein that binds to transforming growth factor (TGF)-β receptor type I and inhibits TGF-β1-induced signalling. [14,15,16] Consistently, inhibition of Smad7 with a specific antisense oligonucleotide (AS) restored TGF-β1 activity and suppressed inflammatory pathways in both in vitro and in vivo models of intestinal inflammation
Phase 1 and phase 2 studies showed that knockdown of Smad7 with a pharmaceutical compound containing the Smad7 AS induced clinical and endoscopic improvement in CD patients, [17, 18] even though a recent phase 3 study was discontinued following a futility analysis showing no benefit in patients treated with such a drug as compared to those receiving placebo. [19]

Summary

Introduction

In Crohn’s disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad, an intracellular inhibitor of the suppressive cytokine TGF-β1. [5] Some demographic, lifestyle-related and clinical factors have been related to increased risk of post-operative recurrence in CD, [6, 7] but the exact basic mechanism underlying CD recurrence remains unknown. In this context, we have recently shown that the mucosa of the neo-terminal ileum after ileocecal resection is infiltrated with immune cells secreting high levels of inflammatory T-helper (Th) type-1-related cytokines before the manifestation of endoscopic. The functional relevance of the TGF-β1 defects in the pathogenesis of CD is supported by studies in mice showing that lack of the cytokine activity is sufficient to promote the development of gut inflammation. The aim of this study was to assess whether Smad induction occurs early and/or late in CD

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