Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances

Zundler, Sebastian; Becker, Emily; Schulze, Lisa Lou; Neurath, Markus F.

doi:10.1136/gutjnl-2018-317977

Cited by 108 publications

(93 citation statements)

References 130 publications

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“…These data demonstrate that molecular MRI of MAdCAM-1 unmasks active inflammation in chronic lesions of the intestinal tract. Overall and in line with our current knowledge of immune cell trafficking in IBD( 6 ), MPIO-αMAdCAM-1 act as leucocyte mimicking particles and display increased binding to the endothelium of the mucosa in both acute and chronic colitis ( Figure 3I ).…”

Section: Resultssupporting

confidence: 82%

“…At the molecular level, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) represents an interesting biomarker for mucosal inflammation( 6 ). Indeed, inflammation in mucosal tissue is associated with several phenotypical changes including activation of the endothelial cells of the lamina propria( 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, inflammation in mucosal tissue is associated with several phenotypical changes including activation of the endothelial cells of the lamina propria( 7 ). Upon activation, these endothelial cells overexpress MAdCAM-1, which is responsible for the trafficking of leucocytes in these tissues( 6 ). Accordingly, MAdCAM-1 is significantly overexpressed in active IBD and vedolizumab, a monoclonal antibody directed against the ligand of MAdCAM-1 (the integrin α4β7), is currently used as a treatment for both Crohn disease and ulcerative colitis.…”

Section: Introductionmentioning

confidence: 99%

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Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Fournier

Lizarrondo

Rateau

et al. 2019

Preprint

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One Sentence Summary: Molecular magnetic resonance imaging allows non-invasive evaluation of mucosal inflammation in clinically relevant experimental models. ABSTRACTMucosal tissues line the digestive, respiratory, urinary, mammary and reproductive tracts and play critical roles in health and disease as the primary barrier between the external world and the inner body. Clinical evaluation of mucosal tissues is currently performed using endoscopy, such as ileocolonoscopy for the intestinal mucosa, that causes significant patient discomfort and can lead to organ damage. Here, we developed a new contrast agent for molecular magnetic resonance imaging (MRI) that is targeted to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), an adhesion molecule overexpressed by inflamed mucosal tissues. We investigated the diagnostic performance of molecular MRI of MAdCAM-1 to detect mucosal inflammation in several models of acute and chronic intestinal inflammation in mice. We demonstrated that molecular MRI of MAdCAM-1 reveals disease activity and can evaluate the response to inflammatory treatments along the whole intestinal mucosa in clinically relevant models of inflammatory bowel diseases. We also provide evidence that this new technique can detect low, subclinical levels of mucosal inflammation.Molecular MRI of MAdCAM-1 has thus potential applications in early diagnosis, longitudinal follow-up and therapeutic response monitoring in diseases affecting mucosal tissues, such as inflammatory bowel diseases.Recently, we and others reported the use of a new family of contrast agents for molecular MRI based on micro-sized particles of iron oxide (MPIO) that displays a dramatically higher sensitivity than classically used nano-sized particles(9-12). Thanks to an artefact known as the blooming effect, MPIO appear around 50 times larger than their actual size on iron sensitive T2*-weighted images (12). This characteristic of MPIO makes them particularly interesting for imaging mucosal tissues, since these tissues measure only a few hundred micrometers of thickness in physiological conditions and are thus hardly visible on unenhanced MRI. In the present study in mice, we developed a new MPIO-based contrast agent for MRI targeted to MAdCAM-1 (thereafter named MPIO-αMAdCAM-1). In three different models of intestinal inflammation, including lipopolysaccharides (LPS) induced endothelial activation, dextran sodium sulfate (DSS) induced colitis and trinitrobenzene sulfonic acid (TNBS) induced colitis(13), we demonstrated that this contrast agent allows detection of mucosal inflammation, quantification of disease activity and assessment of the mucosal response to anti-inflammatory treatments.

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Section: Resultssupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Fournier

Lizarrondo

Rateau

et al. 2019

Preprint

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“…The anti-α4β7 antibody vedolizumab is successfully used for the treatment of IBD since 2014 [3,8] and has been shown to inhibit immune cell homing to the inflamed gut [9,10] indicating that cell trafficking is a central event in the pathogenesis of IBD [11]. Randomized controlled trials [3,8], as well as several real-world cohorts [12][13][14], demonstrated the efficacy and safety of vedolizumab in ulcerative colitis (UC) and Crohn's disease (CD).…”

Section: Introductionmentioning

confidence: 99%

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study

et al. 2020

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Background: While the number of therapeutic options for treating inflammatory bowel diseases (IBD) is increasing, evidence for rational treatment decisions is scarce in many cases. In particular, appropriate biomarkers to predict the response to the anti-α4β7 integrin antibody vedolizumab are currently lacking. Methods:We performed a cohort study with 21 patients suffering from ulcerative colitis (UC), in which first-time treatment with vedolizumab was initiated. CD4 + T cells were isolated from the peripheral blood and dynamic adhesion to recombinant mucosal vascular addressin cell adhesion molecule (MAdCAM-)1 in vitro as well as the effect of vedolizumab on such adhesion in vitro was determined. The expression of α4β1 integrin on peripheral blood CD4 + T cells was quantified by flow cytometry. Electronic patient records were reviewed to determine clinical response to vedolizumab.Results: Dynamic adhesion of peripheral blood CD4 + T cells to MAdCAM-1 and the reduction of adhesion following vedolizumab treatment in vitro were higher and the change in α4β1 expression on CD4 + T cells was different in vedolizumab responders and non-responders. Responders could be identified with high specificity and positive-predictive value. Conclusions: Determining dynamic adhesion of CD4 + T cells to MAdCAM-1 and the in vitro response to vedolizumab before treatment initiation or dynamic integrin regulation in the early course of treatment seem to be promising tools to predict the clinical response to vedolizumab therapy. Larger prospective studies are warranted.

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“…For inflammatory bowel diseases, such as CD and ulcerative colitis, it has been reported that intestinal immune cell trafficking has been identified as a central event in the pathogenesis of diseases. Additionally, cell adhesion is a pivotal step in several aspects of immune cell trafficking [23]. In Fisher, interferon gamma was highly ranked, and the broader concept cytokine was also highly ranked.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive biological interpretation of gene signatures using semantic distributed representation

Okuzono

Hoshino

2019

Preprint

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16Recent rise of microarray and next-generation sequencing in genome-related fields has 17 simplified obtaining gene expression data at whole gene level, and biological interpretation of 18 gene signatures related to life phenomena and diseases has become very important. However, 19 the conventional method is numerical comparison of gene signature, pathway, and gene 20 ontology (GO) overlap and distribution bias, and it is not possible to compare the specificity 21 and importance of genes contained in gene signatures as humans do. 22This study proposes the gene signature vector (GsVec), a unique method for interpreting 23 gene signatures that clarifies the semantic relationship between gene signatures by 24 incorporating a method of distributed document representation from natural language 25 processing (NLP). In proposed algorithm, a gene-topic vector is created by multiplying the 26 feature vector based on the gene's distributed representation by the probability of the gene 27 signature topic and the low frequency of occurrence of the corresponding gene in all gene 28 signatures. These vectors are concatenated for genes included in each gene signature to create 29 a signature vector. The degrees of similarity between signature vectors are obtained from the 30 cosine distances, and the levels of relevance between gene signatures are quantified. 31 Using the above algorithm, GsVec learned approximately 5,000 types of canonical 32 pathway and GO biological process gene signatures published in the Molecular Signatures 33 Database (MSigDB). Then, validation of the pathway database BioCarta with known 3 34biological significance and validation using actual gene expression data (differentially 35 expressed genes) were performed, and both were able to obtain biologically valid results. In 36 addition, the results compared with the pathway enrichment analysis in Fisher's exact test 37 used in the conventional method resulted in equivalent or more biologically valid signatures. 38Furthermore, although NLP is generally developed in Python, GsVec can execute the entire 39 process in only the R language, the main language of bioinformatics. 40 41 4 53 and completeness of human knowledge. Therefore, interpretation is commonly performed by 54 comparing the gene signature, such as differentially expressed genes and gene modules, 55 against a biological gene signature database (such as pathway and GO) and identifying an 56 objective association from a biological perspective [2]. 57 Numerous methodologies for association with pathways have been proposed. Common 58 examples include Fisher's exact test, which is a classical statistical test for the specific overlap 59 of genes; over-representation analysis and gene set enrichment analysis [3], which statistically 60 process the number of overlapping genes and ranking bias by incorporating randomization; 61 and modular enrichment analysis and EnrichNet with graph-based statistics of biological 62 networks [4, 5].63However, these comparisons are numerical, and it is thus not p...

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Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances

Cited by 108 publications

References 130 publications

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Ultrasensitive Molecular Imaging of Mucosal Inflammation Using Leucocyte-Mimicking Particles Targeted to MAdCAM-1

Baseline levels of dynamic CD4+ T cell adhesion to MAdCAM-1 correlate with clinical response to vedolizumab treatment in ulcerative colitis: a cohort study

Comprehensive biological interpretation of gene signatures using semantic distributed representation

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