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Molecular patterns in human ulcerative colitis and correlation with response to infliximab

ABSTRACT: Background & Aims. As a T cell-mediated disease of the colonic epithelium, ulcerative colitis (UC) is likely to share pathogenic elements with other T cell-mediated inflammatory diseases. Recently we showed T cell-mediated rejection of kidney and heart transplants share large scale molecular changes. We hypothesized that UC would manifest a similar disturbance, and that these features would correlate with response to infliximab. Results. UC biopsies manifested coordinate transcript changes resembling rejecting transplants, with T cell, IFNG-induced, macrophage, and injury transcripts increasing while parenchymal transcripts decreased. The disturbance expressed as principal component 1 correlated with conventional assessments e.g. Mayo scores, serum albumin, and lymphoplasmacytic infiltrate. When assessed in published microarray studies, the disturbance predicted response to infliximab: patients with intense disturbance did not achieve clinical response, although quantitative improvement was usually seen even in non-responders. Similar changes were seen in Crohn’s colitis (CDc). Conclusions. The molecular phenotype of UC manifests a large scale coordinate disturbance reflecting changes in inflammatory cells and parenchymal elements that correlates with conventional features and predicts response to infliximab.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51785 | GEO | 2014/12/22

SECONDARY ACCESSION(S): PRJNA225036

REPOSITORIES: GEO

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Molecular patterns in human ulcerative colitis and correlation with response to infliximab

Project description:Background & Aims. As a T cell-mediated disease of the colonic epithelium, ulcerative colitis (UC) is likely to share pathogenic elements with other T cell-mediated inflammatory diseases. Recently we showed T cell-mediated rejection of kidney and heart transplants share large scale molecular changes. We hypothesized that UC would manifest a similar disturbance, and that these features would correlate with response to infliximab. Results. UC biopsies manifested coordinate transcript changes resembling rejecting transplants, with T cell, IFNG-induced, macrophage, and injury transcripts increasing while parenchymal transcripts decreased. The disturbance expressed as principal component 1 correlated with conventional assessments e.g. Mayo scores, serum albumin, and lymphoplasmacytic infiltrate. When assessed in published microarray studies, the disturbance predicted response to infliximab: patients with intense disturbance did not achieve clinical response, although quantitative improvement was usually seen even in non-responders. Similar changes were seen in CrohnM-bM-^@M-^Ys colitis (CDc). Conclusions. The molecular phenotype of UC manifests a large scale coordinate disturbance reflecting changes in inflammatory cells and parenchymal elements that correlates with conventional features and predicts response to infliximab. We studied 56 colon biopsies from patients with colitis, including 43 with UC, characterizing the clinical and histological features, and defined the mRNA phenotype with Affymetrix expression microarrays. We measured the expression of previously defined pathogenesis-based transcript sets representing effector T cells, macrophages, IFNG effects, and parenchymal injury response and dedifferentiation. We also studied 48 microarray files from human colon biopsies from the Gene Expression Omnibus database, classified by response to infliximab therapy to look for molecular changes that predict unresponsiveness.

2014-12-22 | E-GEOD-51785 | biostudies-arrayexpress

Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis

Project description:Infliximab, an anti-TNF-alpha monoclonal antibody, is an effective treatment for ulcerative colitis (UC) with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-TNF-alpha is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in UC. Keywords: drug response Twenty-four patients with active UC, refractory to corticosteroids and/or immunosuppression, underwent colonoscopy with biopsies from diseased colon within a week prior to the first intravenous infusion of 5 mg infliximab per kg body weight. Response to infliximab was defined as endoscopic and histologic healing at 4-6 weeks after first infliximab treatment. Six control patients with normal colonoscopy were included. Total RNA was isolated from colonic mucosal biopsies, labelled and hybridized to Affymetrix Human Genome U133 Plus 2.0 Arrays.

2010-01-06 | E-GEOD-14580 | biostudies-arrayexpress

Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis

2010-01-07 | GSE14580 | GEO

A Predictive Response Signature to Infliximab Treatment in Ulcerative Colitis

2009-08-25 | GSE12251 | GEO

Mucosal expression profiling in patients with inflammatory bowel disease before and after first infliximab treatment

Project description:We used microarrays to identify mucosal gene signatures predictive of response to infliximab (IFX) in patients with inflammatory bowel disease (IBD) and to gain more insight into the pathogenesis of IBD. Keywords: drug response and treatment effect Mucosal biopsies were obtained at endoscopy in actively inflamed mucosa from 61 IBD patients (24 ulcerative colitis (UC), 19 Crohnâs colitis (CDc) and 18 Crohnâs ileitis (CDi)), refractory to corticosteroids and/or immunosuppression, before and 4-6 weeks after (except for 1 CDc patient) their first infliximab infusion and in normal mucosa from 12 control patients (6 colon and 6 ileum). The patients were classified for response to infliximab based on endoscopic and histologic findings at 4-6 weeks after first infliximab treatment. Total RNA was isolated from intestinal mucosal biopsies, labelled and hybridized to Affymetrix Human Genome U133 Plus 2.0 Arrays.

2009-11-02 | E-GEOD-16879 | biostudies-arrayexpress

Transcription profiling of human ulcerative colitis samples reveals a predictive response signature to infliximab treatment in ulcerative colitis

Project description:Infliximab, an anti-TNFa monoclonal antibody, is an effective treatment for ulcerative colitis (UC) inducing over 60% of patients to respond to treatment. Consequently, about 40% of patients do not respond. This study analyzed mucosal gene expression from patients enrolled in ACT1 to provide a predictive response signature for infliximab treatment. Experiment Overall Design: Twenty-two patients underwent colonoscopy with biopsy before infliximab treatment. Response to infliximab was defined as endoscopic and histologic healing at week 8 (P2, 5, 9, 10, 14, 15, 16, 17, 24, 27, 36, and 45 as responders; P3, 12, 13, 19, 28, 29, 32, 33, 34, and 47 as non-responders). Messenger RNA was isolated from pre-infliximab biopsies, labeled and hybridized to Affymetrix HGU133Plus_2.0 Array. The predictive response signature was verified by an independent data set.

2009-09-05 | E-GEOD-12251 | biostudies-arrayexpress

Expression data from colonic biopsy samples of infliximab treated ulcerative colitis patients

Project description:A gene expression profiling sub-study was conducted in which colonic biopsy samples were collected for RNA extraction and hybridization to microarrays from 48 patients with UC who were participating in ACT 1, a placebo-controlled study of infliximab. Gene expression profiles from infliximab responders were compared with those of baseline and infliximab non-responder samples. Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Infliximab non-responders had a molecular phenotype that closely resembled that of untreated patients with UC. Unlike responders, non-responders do not effectively modulate TH1, TH2, and TH17 pathways. Gene expression can differentiate placebo and infliximab responders. Patients with moderate-to-severe, active UC were treated with infliximab or placebo at weeks 0, 2, 6 and every 8 weeks thereafter. Biopsy samples (n=113) were collected from 48 patients at baseline, weeks 8 and 30 for RNA extraction and microarray analysis.

2011-07-21 | E-GEOD-23597 | biostudies-arrayexpress

Expression data from colonic biopsy samples of infliximab treated UC patients

2011-07-22 | GSE23597 | GEO

The effect of vedolizumab (anti-α4β7-integrin) therapy on colonic mucosal gene expression in patients with ulcerative colitis (UC)

Project description:Microarrays were used to investigate the the effect of vedolizumab (VDZ) therapy on colonic mucosal gene expression in UC patients and compared the changes to those observed with infliximab (IFX) therapy.

2016-10-11 | GSE73661 | GEO

A functional genomics predictive network model identifies regulators of inflammatory bowel disease: Mount Sinai Hospital (MSH) Population Specimen Collection and Profiling of Inflammatory Bowel Disease

Project description:This study focuses on inflammatory bowel disease gene expression profiling. Surgical specimens from 134 patients undergoing bowel resection for inflammatory bowel disease (IBD) and non IBD controls at Mount Sinai Medical Center were collected as the source of tissue. Control samples (CLs) were harvested from normal non inflamed bowel located more than 10 cm away from the tumor from patients undergoing bowel resection for sporadic colon cancer. Ulcerative colitis (UC) and Crohn’s (CD) patient samples were all isolated from areas containing moderate to severe inflammation. The diagnostic pathology report for each specimen was provided by the Mount Sinai Hospital Pathology Department. Patients with UC and patients with CD shared common medications including corticosteroids, infliximab, azathioprine, and mesalamine.

2017-07-07 | GSE83687 | GEO

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