P062 Differences in immune cell population subsets in inflammatory bowel disease patients under anti-TNF treatment

Background & Aims Anti-tumour necrosis factor-alpha (anti-TNFα) agents have been used for inflammatory bowel disease (IBD), however, it has up to 30% non-response rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNFα treatment are clearly needed. Methods Publicly available transcriptomic data from IBD patients receiving anti-TNFα therapy was systemically collected and integrated. In silico flow cytometry approaches and MetaScape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti TNFα-treated animal model (with lipopolysaccharide (LPS)-induced inflammation). The receiver operating characteristic (ROC) curve was applied to all genes to identify the best prediction biomarkers. Results A total of 449 samples were retrieved from control, baseline and after primary anti-TNFα therapy or placebo. No statistically significant differences were observed between anti-TNFα treatment responders and non-responders at baseline in immune microenvironment scores. Neutrophils, endothelial and B cell populations were higher in baseline non-responders and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly up-regulated in LPS-induced neutrophils but no statistically significant changes were observed in neutrophils treated with anti-TNFα. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (ROC: 80.7%, 95% CI: 73.8% - 87.5%) with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in non-responders compared to responders (p < 0.0001). Conclusions Hyperactive chemotaxis influences responses to anti TNFα treatment and IL13RA2 is a potential biomarker to predict anti-TNFα treatment response.

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Faculty Opinions recommendation of Checkpoint Inhibitor Colitis Shows Drug-Specific Differences in Immune Cell Reaction That Overlap With Inflammatory Bowel Disease and Predict Response to Colitis Therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739510767.793584679 ◽

2021 ◽

Author(s):

Noam Harpaz ◽

Alexandros D. Polydorides

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Immune Cell ◽

Checkpoint Inhibitor ◽

Cell Reaction ◽

Inflammatory Bowel

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OP33 Multi-omics analysis reveals specific bio-geographical and functional characteristics in inflammatory bowel disease intestinal mucosa

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.032 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S031-S034

Author(s):

N Maimon ◽

S Gerassy-Vainberg ◽

H Bar-Yosef ◽

A Alpert ◽

E Starosvetsky ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Immune Cell ◽

Response To Therapy ◽

Anatomical Location ◽

Specific Cell ◽

Cell Composition ◽

Dominant Feature ◽

Inflammatory Bowel

Abstract Background Anatomical location and extent of disease are main factors that affect inflammatory bowel disease (IBD) course and prognosis. No explanation is available for segmental intestinal involvement in either Crohn’s disease (CD) or ulcerative colitis (UC), or for selective segmental response to therapy or disease complications. Therefore, studying the cellular composition of different intestinal segments may provide pathophysiological insights into these phenomena. Methods We compared location-specific cell composition and function by Cytometry Time-of-Flight (CyTOF), gene expression and single-cell (sc) RNAseq data obtained from 3 independent cohorts of healthy donors and IBD patients during remission and flare-ups. Using CyTOF data (n = 38 biopsies), we built a high-resolution screening of immune cell behaviour along the intestine. We validated the findings with gene expression data of 370 samples, and expanded screening resolution by computational methodologies. We then tested a specific pathway in scRNAseq data (n = 10 paired biopsies from 5 patients) and validated its significance by cell-specific Significance Analysis of Microarrays (csSAM). Results We found a location along the intestine to be a dominant feature determining immune and non-immune cell composition. We observed that inflammation reduced anatomic segregation beyond cell infiltration, and decreased the ability to cope with oxidative stress. An upregulated IL-6 pathway in T regulatory cells in UC patients was recognised as sigmoid-specific compared with known inflammatory IL-6 roles in macrophages, as seen in the right colon. This observation may be linked to colonic perforations associated with anti-IL-6R treatment. Suppressor of cytokine signalling 3 (SOCS3) may control IL-6 location-specific action. Conclusion Our study displays a unique and comprehensive cell map of IBD in a location-specific context, providing potential explanations to unexplained clinical phenomena. These observations may allow to tailor therapies to affected areas with improved therapeutic index and efficacy.

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Targeting immune cell circuits and trafficking in inflammatory bowel disease

Nature Immunology ◽

10.1038/s41590-019-0415-0 ◽

2019 ◽

Vol 20 (8) ◽

pp. 970-979 ◽

Cited By ~ 68

Author(s):

Markus F. Neurath

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Immune Cell ◽

Inflammatory Bowel

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Immunopathogenesis of Inflammatory Bowel Disease: Role of Cytokines and Immune Cell-Enterocyte Interactions

Nestl� Nutrition Workshop Series: Clinical & Performance Program - Inflammatory Bowel Diseases ◽

10.1159/000061779 ◽

1999 ◽

pp. 41-62 ◽

Cited By ~ 13

Author(s):

Serge Dionne ◽

Frank M. Ruemmele ◽

Ernest G. Seidman

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Immune Cell ◽

Inflammatory Bowel

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OP27 High-dimensional mass cytometry reveals the immune cell landscape in inflammatory bowel disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjy222.026 ◽

2019 ◽

Vol 13 (Supplement_1) ◽

pp. S020-S020

Author(s):

V van Unen ◽

N Li ◽

T Abdelaal ◽

Y Kooy-Winkelaar ◽

L Ouboter ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Immune Cell ◽

High Dimensional ◽

Mass Cytometry ◽

Inflammatory Bowel

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Metallothionein: A Novel Therapeutic Target for Treatment of Inflammatory Bowel Disease

Current Pharmaceutical Design ◽

10.2174/1381612824666180717110236 ◽

2018 ◽

Vol 24 (27) ◽

pp. 3155-3161 ◽

Cited By ~ 4

Author(s):

Kristen E. Dostie ◽

Amy V. Thees ◽

Michael A. Lynes

Keyword(s):

Inflammatory Bowel Disease ◽

Stress Response ◽

Bowel Disease ◽

Immune Cell ◽

Inflammatory Responses ◽

Cytokine Therapy ◽

Murine Models ◽

Inflammatory Stress ◽

Inflammatory Bowel ◽

Novel Therapeutic

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic inflammation within the gastrointestinal tract. It is a multifactorial disease associated with immune-cell mediated oxidative damage to the intestinal mucosa. There is no cure for IBD, but anti-cytokine therapy can limit target inflammation and disease progression. Unfortunately, many patients are nonresponsive or develop resistance to anti-cytokine therapy over time creating a need for new therapeutic agents. Metallothionein (MT) is a small, highly conserved stress response protein that has been shown to modulate the immune response as a pro-inflammatory agent, regulates divalent heavy metal homeostasis, and acts as a reactive metabolite scavenger. Our research, as well as other groups studying MT, has described MT induction and release during IBD inflammatory stress response. The release of MT results in activation of inflammatory responses leading to progressive inflammation and subsequent expansion of MT synthesis. A monoclonal antibody specific for MT has been used in murine models of IBD and should only target the extracellular pool of MT, thus representing a novel therapeutic approach to this disease.

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