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Immune System Diseases

Digestive System Disorders

Small molecule drug

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Immune System Diseases	1

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NOD1 x NOD2	1

AbstractBackgroundEvolution of Crohn’s disease (CD) is often marked by fibrostenotic complications and available biotherapies cannot prevent or treat intestinal fibrosis. The pathophysiological mechanisms of intestinal fibrosis are multiple and poorly understood. The intestinal epithelium probably plays a key role. The endoplasmic reticulum stress (ERS) is involved in the pathophysiology of IBD and in fibrosis. Protein disulfide isomerases (PDIs) take part in the ER stress response, but their precise roles and associations with CD remain poorly characterized. We investigated the distribution of selected PDIs within the ileum and colon of adult and pediatric patients with inflammatory or stenosing CD.MethodsTissues from 72 pediatric and 47 adult CDs, and 26 pediatric and 48 adult patients without IBD were included from 4 tertiary hospitals. The degree of fibrosis and inflammatory infiltrate were evaluated. The distribution of 4 PDIs (AGR2, BiP, PDIA6, ERP44) within the tissues was studied by immunohistochemistry (IHC) using a semiquantitative scoring scale (0 to 4). Statistical tests used were ANOVA or Kruskal-Wallis (with post hoc test), T-Student and Mann-Whitney.ResultsThe clinical characteristics of the patients included are described in Table 1. The PDIs provide an IHC signal which was mainly epithelial. The distribution of PDIs differed according to the segment studied (colon or ileum), the age of CD onset, location in the epithelium (surface, median crypt, or bottom of crypt), and the normal, inflammatory, and/or fibrotic features of the tissues. In the ileum of adult and pediatric CDs, the distribution of AGR2 was significantly higher in the epithelium adjacent to fibro-inflammatory tissues (p<0.01). In pediatric cases, AGR2 increased significantly with the fibrosis grade within the surface epithelium of the ileum (Fig. 1). The distributions of the other PDIs (BiP, ERP44 and PDIA6) were rather influenced by the inflammatory infiltrates and varied in adult and pediatric CD. The distribution of BiP was significantly higher in tissues with acute and/or chronic inflammation and independent from fibrosis. In adults, the distribution of PDIA6 in the colonic epithelium was significantly higher in CD cases compared to non-CD cases.ConclusionOur results suggest that the studied PDIs may have different roles in the ERS response within the intestinal epithelium in adult and pediatric CD. These PDIs need to be functionally explored further to better understand their specific involvement in inflammation and fibrosis in CD. The increase of AGR2 in fibro-inflammatory tissues, not observed with other PDIs, suggests a specific link between AGR2 and intestinal fibrosis.

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Pipeline

Pipeline Snapshot as of 21 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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