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Transcriptional behavior of regulatory T cells predicts IBD patient responses to vedolizumab therapy

ABSTRACT: Vedolizumab (VDZ) is used to treat patients with IBD but the exact way it works is not known. We studied the immune system in the blood and intestine of patients treated with VDZ and found immune characteristics that correlated with response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184593 | GEO | 2022/08/23

REPOSITORIES: GEO

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Transcriptional behavior of regulatory T cells predicts IBD patient responses to vedolizumab therapy

Project description:Transcriptional behavior of regulatory T cells predicts IBD patient responses to vedolizumab therapy

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Predicting response to vedolizumab therapy using mucosal transcriptomics in IBD patients

Project description:In this study we wanted to identify baseline predictors of successful vedolizumab therapy in patients with inflammatory bowel disease.

2019-08-23 | E-MTAB-7845 | biostudies-arrayexpress

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.

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Predicting response to vedolizumab therapy using mucosal transcriptomics in IBD patients

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Vedolizumab efficacy is associated with decreased intracolonic dendritic cells, not memory T cells [P444]

Project description:Background: Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn’s disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. Methods: We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect resolving inflammation could have on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 71 case patients receiving vedolizumab were matched with biopsies from 71 control patients, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full mRNA transcriptome sequencing of sorted T cells. Results: No difference was seen between vedolizumab recipients and controls in the quantity of any antigen-experienced lymphocyte subset, nor the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than controls, regardless of response. The only immune population that was significantly reduced exclusively in the colonic mucosa of vedolizumab-responsive patients was CD1c+ (BDCA1+) dendritic cells. In blood, these dendritic cells ubiquitously express more α4β7 per cell than almost any other circulating leukocyte, but rapidly downregulate α4β7 expression upon vedolizumab exposure. Conclusions: The clinical efficacy of vedolizumab thus reveals integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to IBD pathogenesis.

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Vedolizumab efficacy is associated with decreased intracolonic dendritic cells, not memory T cells [P430]

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Responsiveness to vedolizumab therapy in ulcerative colitis is associated with alterations in immune cell-cell communications

Project description:Ulcerative colitis (UC) is a major subtype of inflammatory bowel disease (IBD), a spectrum of chronic intestinal disorders caused by dysregulated immune responses to gut microbiota. Although transcriptional and functional changes in a number of immune cell types have been implicated in the pathogenesis of IBD, the cellular interactions and signals that drive these changes have been less well-studied. Moreover, the precise mechanisms of action underlying many biologic therapies, including the anti-47 integrin antagonist vedolizumab, remain incompletely understood. Our study aimed to explore possible additional mechanisms through which vedolizumab acts.

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Differential effects of ontamalimab versus vedolizumab on immune cell trafficking in intestinal inflammation and IBD

Project description:Differential effects of ontamalimab versus vedolizumab on immune cell trafficking in intestinal inflammation and IBD

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Transcriptional Behavior of Regulatory T Cells Predicts IBD Patient Responses to Vedolizumab Therapy.

Project description:BackgroundInflammatory bowel disease (IBD) involves chronic T cell-mediated inflammatory responses. Vedolizumab (VDZ), a monoclonal antibody against α4β7 integrin, inhibits lymphocyte extravasation into intestinal mucosae and is effective in ulcerative colitis (UC) and Crohn's disease (CD).AimWe sought to identify immune cell phenotypic and gene expression signatures that related to response to VDZ.MethodsPeripheral blood (PBMC) and lamina propria mononuclear cells (LPMCs) were analyzed by flow cytometry and Cytofkit. Sorted CD4 + memory (Tmem) or regulatory T (Treg) cells from PBMC and LPMC were analyzed by RNA sequencing (RNA-seq). Clinical response (≥2-point drop in partial Mayo scores [UC] or Harvey-Bradshaw index [CD]) was assessed 14 to 22 weeks after VDZ initiation. Machine-learning models were used to infer combinatorial traits that predicted response to VDZ.ResultsSeventy-one patients were enrolled: 37 received VDZ and 21 patients remained on VDZ >2 years. Fourteen of 37 patients (38%; 8 UC, 6 CD) responded to VDZ. Immune cell phenotypes and CD4 + Tmem and Treg transcriptional behaviors were most divergent between the ileum and colon, irrespective of IBD subtype or inflammation status. Vedolizumab treatment had the greatest impact on Treg metabolic pathways, and response was associated with increased expression of genes involved in oxidative phosphorylation. The strongest clinical predictor of VDZ efficacy was concurrent use of thiopurines. Mucosal tissues offered the greatest number of response-predictive biomarkers, whereas PBMC Treg-expressed genes were the best predictors in combinatorial models of response.ConclusionsMucosal and peripheral blood immune cell phenotypes and transcriptional profiles can inform VDZ efficacy and inform new opportunities for combination therapies.

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Differential effects of ontamalimab versus vedolizumab on immune cell trafficking in intestinal inflammation and IBD

Project description:The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in UC and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab.

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