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NOVEL TRANSCRIPTIONAL SIGNATURE OF CIRCULATING MONOCYTES DEFINES RESPONSE TO ADVANCED THERAPIES IN INFLAMMATORY BOWEL DISEASE

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NOVEL TRANSCRIPTIONAL SIGNATURE OF CIRCULATING MONOCYTES DEFINES RESPONSE TO ADVANCED THERAPIES IN INFLAMMATORY BOWEL DISEASE

Asma Amamou 1, Cian O'Mahony 1, Jan Toman 1, Aida Lopez Espinar 2, Alan Deery 1, Piotr Kowalski 3, Marietta Iacucci 1, Subrata Ghosh 1

Affiliations

1 APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland

2 School of Pharmacy, University College Cork, Cork, Ireland

3 APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland|||School of Pharmacy, University College Cork, Cork, Ireland

Summary

AI Generated

Helios expression in circulating monocytes at baseline and after induction therapy distinguishes super-responders from non-responders to advanced IBD therapies, with Helios re-emerging in 34.14% of super-responder monocytes but remaining absent in non-responders.

IBD patients had higher circulating monocyte counts at baseline compared to healthy controls (p<0.001), with levels decreasing significantly in super-responders but remaining elevated in non-responders at weeks 8-12.
Helios expression was absent in IBD patient monocytes at baseline (47.31% in healthy controls) and re-emerged in 34.14% of super-responder monocytes by weeks 8-12 but remained undetectable in non-responders.
Non-classical monocytes (CD14⁻CD16⁺) were increased in IBD patients at baseline versus healthy controls (p<0.05) and persisted in non-responders versus super-responders at weeks 8-12 (p<0.05).
In vitro functional studies showed Ikaros silencing reduced pro-inflammatory markers, IL6 and IL1β secretion, and phagocytosis in response to LPS, while Helios silencing increased macrophage activation and pro-inflammatory markers in response to IL10.
Macrophages treated with LPS+IFNγ or TPP upregulated Ikaros, STAT1, and CXCL10 (p<0.01), while Helios, TGM2, and MCR1 were upregulated in response to IL10 (p<0.05), confirming opposing roles in macrophage polarization.

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Abstract

Introduction

Treatment response in inflammatory bowel disease (IBD) is highly variable, with an urgent need for biomarkers to guide therapeutic decisions. Circulating monocytes, key players in intestinal immunity, act as precursors to tissue macrophages and contribute to inflammation and mucosal healing. The transcriptional programs that govern monocyte fate and their association with treatment outcomes remain poorly defined. Ikaros family proteins regulate gene expression through distinct mechanisms in lymphocytes, but little is known about their role in monocyte-macrophage function in IBD. We aimed to investigate the role of Ikaros family (Ikaros, Helios, Aiolos, Eos, Pegasus) in shaping monocyte function linked to advanced therapies response.

Aims & Methods

Peripheral blood samples were collected at baseline (W0) and after 8-12 weeks of induction therapy (W8/12) from IBD patients who initiated or switched advanced therapy [biologics, oral synthetics] and from healthy controls (HC) (n=8). We included patients achieving clinical remission after induction [Super-Responders] SR (n=18) and those showing no response [Non-Responders] NR (n=16). Immune phenotype and expression of Ikaros proteins were assessed via multiparametric flow cytometry (FACS) and correlated with clinical outcomes. To assess functional roles of Ikaros proteins, monocyte-derived macrophages were generated in vitro from buffy coat (n=6). Cells were polarised using cytokine cocktails to induce pro-inflammatory (LPS+IFNγ or TNF+PGE2+Pam3CSK4; TPP), alternative (IL1β+LPS), or regulatory (IL10) phenotypes. siRNA-loaded nanoparticles were used to silence Ikaros or Helios prior to polarisation. Phenotypic changes were analysed by FACS; cytokines secretion by ELISA; genes expression by qPCR; and phagocytosis by fluorescent beads uptake.

Results

At W0, IBD patients exhibited a significant increase in circulating monocyte counts (vs HC, p<0.001). At W8/12, monocyte levels significantly decreased in the SR group, while remaining elevated in the NR group. FACS analysis revealed an increased proportion of non-classical monocytes (CD14⁻CD16⁺) in the IBD group at W0 (vs HC; p< 0.05), persisting in NR at W8/12 (vs SR; p<0.05). IBD monocytes also showed higher expression of CCR2 and CX3CR1 compared to HC. Helios expression was absent in monocytes from IBD patients at W0, while the mean expression of Helios was 47.31% in monocytes from the HC group. At W8/12, Helios expression re-emerged in 34.14% of monocytes derived from the SR patients but remained undetectable in the NR. In vitro, macrophages treated with LPS+IFNγ or TPP upregulated Ikaros, STAT1, and CXCL10 gene expression (p< 0.01), while Helios, TGM2, and MCR1 were upregulated in response to IL10 (p< 0.05). Helios expression was absent in TNF-stimulated macrophages. Ikaros silencing reduced pro-inflammatory markers, IL6 and IL1β cytokines secretion, and inhibited phagocytosis in response to LPS, whereas Helios silencing increased macrophages activation, and pro-inflammatory markers in response to IL10.

Conclusion

Monocyte subsets distribution and Helios, Ikaros expression dynamics clearly distinguished SR from NR in IBD. Sustained absence of Helios and persistence of non-classical monocytes in NR suggest a failure to transition toward a regulatory phenotype. This may further contribute to altered migratory capacity and influence their functional fate within intestinal tissue. Functional assays confirm opposing roles of Ikaros and Helios in the macrophages activation, underscoring their unique potential as biomarkers or therapeutic targets to modulate inflammation in IBD.

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Predicting response to IBD therapy

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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COMBINED TNF AND OX40L BLOCKADE DEMONSTRATES EFFICACY IN A MURINE ADOPTIVE T CELL TRANSFER MODEL OF COLITIS

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COMBINED TNF AND OX40L BLOCKADE DEMONSTRATES EFFICACY IN A MURINE ADOPTIVE T CELL TRANSFER MODEL OF COLITIS

Thomas Leeuw 1, Rolf Keiffer 1, Danping Ding-Pfennigdorff 1, Christian Asbrand 1, Raaj Mehta 2, Matthias Herrmann 1

Affiliations

1 Immunology & Inflammation Research TA, Sanofi Germany, Frankfurt, Germany

2 Immunology & Inflammation TA, Sanofi US, Cambridge, United States

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Abstract

Introduction

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are characterized by dysregulated T-cell responses, causing chronic intestinal inflammation.¹ While anti-TNF therapy is established in IBD, targeting additional pathways may improve outcomes for patients who do not respond adequately to current treatments.² OX40L, an immune co-stimulator, has been implicated in the pathogenesis of several inflammatory conditions.³ Our study provides a comprehensive analysis of the effects of combined TNF and OX40L blockade in a murine adoptive T cell transfer (ATC) model of colitis, examining body weight, detailed histopathological parameters, and a broad range of inflammatory cytokines in colon tissue.

Aims & Methods

Colitis was induced in severe combined immunodeficiency (SCID) mice by intraperitoneal transfer of CD4⁺CD45RB^high T cells isolated from healthy BALB/c donor mice. We established five treatment groups (n=8-10): 1) CD45RB^low transfer “healthy control”, 2) CD45RB^high transfer with isotype antibodies “disease control group”, 3) CD45RB^high transfer with anti-TNF antibody (XT3.11, 250 μg/mouse), 4) CD45RB^high transfer with anti-OX40L antibody (RM134L, 250 μg/mouse), and 5) CD45RB^high transfer with both antibodies at 250 µg/mouse, each. Body weight was monitored for 46 days as a measure of disease progression and normalized to baseline weight at day 1. At study termination, we collected colon tissue for analysis of inflammatory cytokines using multiplex immunoassays and conducted histopathological examination. Histopathological scoring was performed blinded using a validated scoring system for colonic inflammation.⁴

Results

Overall, combined anti-TNF/anti-OX40L therapy was most effective in preventing body weight loss compared to the isotype disease control group, followed by anti-TNF monotherapy and anti-OX40L monotherapy (p<0.0001, p=0.0009, and p=0.03, respectively). Mean normalized body weight (MNBW) of the CD45RB^low healthy control group at termination on day 46 was 115.2 %, while CD45RB^high cell transfer in the disease control group triggered disease induction and body weight loss, with a MNBW of 93.8 % at day 46. The CD45RB^high groups treated with anti-TNF or anti OX40L monotherapy reached a MNBW of 107.6 % and 102.9%, respectively. The CD45RB^high group treated with combination therapy reached 112.6%, closest to the CD45RB^low healthy control group. Notably, only combination therapy led to a significant improvement in histopathological scoring (p=0.0176) compared to the isotype disease control. Similarly, combination treatment consistently resulted in the strongest downregulation of several inflammatory cytokines including IFNg, IL-4, or TNFa, which are increased in colon tissue in the CD45RB^high disease group compared to the CD45RB^low healthy control group.

Conclusion

Combined blockade of TNF and OX40L demonstrated significantly greater efficacy in the ATC preclinical model of IBD in prevention of weight loss, downregulation of key inflammatory cytokines, and reduction of histological damage compared to either monotherapy. These data suggest potential additive efficacy for TNF and OX40L inhibition in controlling intestinal inflammation, and warrant further exploration of dual TNF/OX40L inhibition in clinical trials, particularly among those with inadequate response to anti-TNF monotherapy.

References

1. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
2. Vermeire S. Combination biologic therapy for ulcerative colitis. Lancet Gastroenterol Hepatol. 2023;8:288-90.
3. Fu Y, Lin Q, Zhang Z, Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B. 2020;10:414-33.
4. Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, Zeitz M, Siegmund B, Kühl AA. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7:4557-76.

Disclosure

Thomas Leeuw, Rolf Keiffer, Danping Ding-Pfennigdorff, Christian Asbrand, Raaj Mehta, Matthias Herrmann are employees of Sanofi and may hold stock or equity options in Sanofi

Event

UEG Week Berlin 2025

Topics

IBD Immunology Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Unexpected novel therapies tackling intestinal inflammation

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Personalising treatment: Tailoring to precision

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Personalising treatment: Tailoring to precision

Francesco Sclafani 1

Affiliations

1 Université libre de Bruxelles, Bruxelles, Belgium

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Abstract

Event

UEG Week Berlin 2025

Topics

Colorectal Digestive Oncology Mechanisms & Personalised Medicine

Session

Catching up with every day's practise in colorectal cancer treatment

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Advancing IBD precision medicine: The next frontier

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Advancing IBD precision medicine: The next frontier

Bram Verstockt 1

Affiliations

1 University Hospitals Leuven and KU Leuven, Translational Research in Gastrointestinal Disorders - IB, Leuven, Belgium

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Abstract

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Session

The art of making clinical research precise: Predicting therapy response in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Predicting therapy response in HCC and CCC

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UEG Presentation

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Predicting therapy response in HCC and CCC

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

Predicting therapy response in HCC and CCC

Max Seidensticker 1

Affiliations

1 LMU München, Munich, Germany

Summary

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Summary is not available for this content yet.

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Abstract

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Hepatobiliary Mechanisms & Personalised Medicine

Session

Predicting therapy response

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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COMBINED TNF AND OX40L BLOCKADE DEMONSTRATES EFFICACY IN A MURINE ADOPTIVE T CELL TRANSFER MODEL OF COLITIS

Matthias Herrmann

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UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

Symptomatic gallstones

Philip de Reuver 1

Affiliations

1 Radboudumc, Nijmegen, Netherlands

Summary

AI Generated

Summary is not available for this content yet.

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Abstract

Event

UEG Week Berlin 2025

Topics

Colorectal Hepatobiliary Primary Care

Session

Cross-cutting: Management changes in high prevalence problems

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

COMBINED TNF AND OX40L BLOCKADE DEMONSTRATES EFFICACY IN A MURINE ADOPTIVE T CELL TRANSFER MODEL OF COLITIS

Matthias Herrmann

Personalising treatment: Tailoring to precision

Francesco Sclafani

Advancing IBD precision medicine: The next frontier

Bram Verstockt

Predicting therapy response in HCC and CCC

Max Seidensticker

Symptomatic gallstones

Philip de Reuver

Anastomotic leakage in the gut

Nuha Yassin

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

Anastomotic leakage in the gut

Nuha Yassin 1

Affiliations

1 St Mark'S Hospital, London, London, United Kingdom

Summary

AI Generated

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Abstract

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Pancreas Surgery

Session

Post-OP complications: When do we need to step in?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Matthias Herrmann

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Francesco Sclafani

Advancing IBD precision medicine: The next frontier

Bram Verstockt

Predicting therapy response in HCC and CCC

Max Seidensticker

Symptomatic gallstones

Philip de Reuver

Anastomotic leakage in the gut

Nuha Yassin