Fellowships & Grants Synopsis Reports

17December2019

ECCO Grant Study Synopsis: Petra Bacher

Petra Bacher, ECCO Grant Awardee

The immune repertoire of microbe-reactive T cells in blood and tissue of IBD patients

 

Petra Bacher
© 
Petra Bacher

Aim of Research

Dysregulated T cell reactions against intestinal antigens are considered to be a causal or driving factor for Inflammatory Bowel Diseases (IBD). So far, technical limitations concerning the detection and characterisation of microbiota-reactive T cells have prevented determination of the exact contribution of specific T cell subsets against individual microbes to the intestinal balance and its dysregulation in IBD. Analysing the phenotype, function and T cell receptor (TCR) repertoire of microbe-specific T cells in blood and intestinal mucosa of IBD patients will therefore provide important insights to fundamental questions on the clonal expansion of pro- and anti-inflammatory microbe-reactive T cells, their clonal relation and stability and the sites (blood and/ or intestinal tissue) at which the relevant T cell subsets are located.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 14, Issue 4

17December2019

ECCO Grant Study Synopsis: Lissy de Ridder

Lissy de Ridder, ECCO Grant Awardee

Infliximab in Paediatric Crohn’s Disease; in whom to start (ImProve)

 

Lissy de Ridder
© 
Lissy de Ridder

Aim of Research

Crohn’s Disease (CD) is a heterogeneous chronic immune-mediated inflammatory disease. To improve management, precision medicine is urgently needed to target the underlying pathogenic immune response that is driving disease. There is a key unmet need to identify biomarkers that will predict the need for, and the response to, anti-tumor necrosis factor (TNF) treatment, including in paediatric CD. This constitutes the aim of the present project. The use of such predictive biomarkers will help to avoid delay in effective treatment, complications due to ongoing inflammation and exposure of non-responders to anti-TNF. We hypothesise that genetic expression profiling, in combination with thorough patient characterisation, will lead to such biomarkers and thereby improve targeted anti-TNF use in paediatric CD.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 14, Issue 4

11October2019

ECCO Fellowship Study Synopsis: Ramona Bruckner

Ramona Bruckner, ECCO'19 Fellowship Awardee

The role of fibroblasts in the pathogenesis of Crohn’s Disease-associated fistulas and in mesenchymal stem cell therapy  

 


Ramona Bruckner
© 
Ramona Bruckner

Aim of the research

Perianal fistulas are a severe and frequent complication in Crohn’s Disease (CD) patients, significantly affecting their quality of life. High recurrence rates, incomplete fistula healing and non-responding patients make the treatment challenging. Despite some novel insights, current knowledge about the pathogenesis of fistula formation is still limited. Fibroblasts are abundantly present in fistulas and were recently reported to regulate Th1 cell activity in Inflammatory Bowel Disease (IBD). Our hypothesis is that fibroblasts act as the key drivers of this disease complication by regulating inflammatory cell recruitment. We will investigate which pro-inflammatory cytokines and chemoattractants are produced by fistula-derived fibroblasts and how they influence recruitment of immune cells, leading to sustained inflammation. Our second hypothesis is that mesenchymal stem cells (MSCs) can normalise this fibroblast-driven pro-inflammatory environment.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 14, Issue 3

11October2019

ECCO Fellowship Study Synopsis: Javier Conde Aranda

Javier Conde Aranda, ECCO'19 Fellowship Awardee

PTPN2 and TiO2 in the pathogenesis of Inflammatory Bowel Disease  

 

conde arandaJavier Conde Aranda
© 
Javier Conde Aranda

Aim of the research

Titanium dioxide (TiO2) may play a pivotal role in the onset and perpetuation of chronic intestinal inflammation. These effects may be genetically triggered, and variations in IBD risk genes, such as PTPN2, may contribute critically to the detrimental effect of TiO2 in vivo. For these reasons, we will study the combined effects of the presence of disease-associated genetic PTPN2 variations and TiO2 microparticles on the development of chronic intestinal inflammation and on inflammasome activity, as well as the subsequent consequences for the host immune system, in particular innate immune responses. The study will demonstrate the relevance of TiO2 in the pathogenesis of intestinal inflammation in vivo. To address the aforementioned aims, we will:

1. Analyse whether PTPN2-mediated inflammasome activation can control TiO2-induced intestinal inflammation.
2. Demonstrate whether the presence of the disease-associated PTPN2 variant affects NLRP3 inflammasome activation and intestinal inflammatory responses to TiO2 in IBD patients.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 14, Issue 3

11December2018

ECCO Grant Study Synopsis: Federica Ungaro

Federica Ungaro, ECCO Grant Winner

Definition of IBD-associated gut virome via next-generation sequencing: Novel insights for disease onset and treatments

 

Federica UngaroFederica Ungaro
© Federica Ungaro

Aim of Research

Viral infections have been reported to be the primary trigger in many diseases. Preliminary results from RNA-seq analysis performed on mucosal biopsies of patients with active Crohn’s Disease (CD) or Ulcerative Colitis (UC) and healthy controls revealed indicated an IBD-specific viral signature, characterised by increased levels of viral RNAs, especially in patients with UC.

Although analyses on gut virome composition are available, to date nobody has described which viruses are involved in IBD onset. We propose characterising the viral composition of gut mucosal samples from early-diagnosed patients with IBD and healthy subjects by exploiting transcriptomic analysis. Moreover, through RNA silencing experiments, we will investigate whether the inhibition of viral-specific RNAs may be beneficial in mucosal biopsies from patients with active IBD. Results obtained from this study are expected to lead to the unveiling of a novel concept depicting IBD aetiopathogenesis as related to specific viral infections. This will arguably offer new therapeutic insights and promote the search for antiviral drugs for the treatment of IBD.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 13, Issue 4

11December2018

ECCO Grant Study Synopsis: Dina Danso-Abeam

Dina Danso-Abeam, ECCO Grant Winner

Identification of the functional role of NLRP6 in human Crohn’s Disease

 

03 SciCom 8 8 Danso Abeam Dina MASTER ECCO Grant synopsis rounded Dina Danso-Abeam
© Dina Danso-Abeam

Aim of Research

The introduction of biological therapies such as anti-TNF has led to a decrease in surgery in IBD. However, many patients do not benefit from this treatment: One-third of patients do not respond to induction therapy (primary non-responders) and about half of primary responders lose response over time (secondary non-responders). This is in part due to therapeutic targeting of generalised inflammation rather than specific targeting of well-defined molecular mediators of IBD pathogenesis.

Most recently, the nod-like receptor NLRP6 has come to light for its potential role in local inflammation driven by gut microbial dysbiosis, albeit almost all data are emerging from mouse models. Our preliminary data from a patient harbouring a novel NLRP6 mutation show significant dysregulation in multiple immune cells, providing strong evidence for the role of NLRP6 in immune homeostasis. Taking into account the high expression of NLRP6 in human intestine, this project aims to decipher the role of NLRP6 in the pathology of Crohn’s Disease (CD).

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 13, Issue 4

11December2018

ECCO Grant Study Synopsis: Holm Uhlig

Holm Uhlig, ECCO Grant Winner and Sumeet Pandey

Neuro-immune interactions in gut macrophages

 

Holm UhligHolm Uhlig
© Holm Uhlig

Inflammatory Bowel Diseases (Crohn’s Disease and Ulcerative Colitis) are polygenic and multifactorial disorders caused by aberrant responses to the intestinal microbiota. Crohn’s Disease in particular is associated with defective bacterial handling in phagocytes (i.e. monocytes and macrophages), which digest bacteria by the process known as autophagy/xenophagy. Monocyte/macrophage function is modulated by the surrounding microenviroment, in which pathogens, metabolites, chemokines and cytokines are present.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 13, Issue 4

11December2018

ECCO Grant Study Synopsis: Patrick van Rheenen

Patrick van Rheenen, ECCO Grant Winner and Sjoukje Haisma, PhD candidate

Identification of rare genetic variants contributing to the development of childhood-onset IBD-PSC using parent-offspring trios

 

Patrick van RheenenPatrick van Rheenen
© Patrick van Rheenen

Primary Sclerosing Cholangitis (PSC) is a rare and severe disease leading to fibrotic destruction of the bile ducts. The majority of childhood-onset cases are associated with Inflammatory Bowel Disease, Ulcerative Colitis in particular.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 13, Issue 4

11December2018

ECCO Grant Study Synopsis: Janneke N. Samsom

Janneke N. Samsom, ECCO Grant Winner

TIGIT+CD38+ effector cells: New players in suppressing inflammation in IBD?

 

03 SciCom 5 5 Samson Janneke MASTER ECCO Grant synopsisJanneke N. Samsom 
© Janneke N. Samsom 

Background and Hypothesis

In Inflammatory Bowel Disease (IBD), T-cell reactivity against harmless microbial antigens drives chronic inflammation. After induction of remission, patients receive T-cell-suppressing maintenance treatment, which is effective in maintaining remission in some patients but not others. “T-cell immunoglobulin and ITIM domain” (TIGIT) is a novel inhibitor of T-cell activation. Preliminary experiments show that human circulating TIGIT-expressing CD38+ effector T cells are concomitantly enriched in the inhibitory molecules IL-10, PD-1 and CTLA-4. Crucially, frequencies of these cells were much reduced in a subgroup of paediatric IBD patients at disease onset and associated with reduced duration of clinical remission during follow-up.

We hypothesise that TIGIT+CD38+ effector T cells are functionally involved in immune regulation of microbial responses in the gastrointestinal tract.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 13, Issue 4

11December2018

ECCO Grant Study Synopsis: Stefan Koch

Stefan Koch, ECCO Grant Winner

Regulation of intestinal epithelial homeostasis by Cyclin Y

 

03 SciCom 4 4 Koch Stefan MASTER ECCO Grant synopsis roundedStefan Koch
© Stefan Koch

Aim of Research

Genetic predisposition contributes to the development of Inflammatory Bowel Diseases (IBD). Prior GWAS studies have identified numerous IBD risk loci, but most of them have no assigned function to date. The aim of this study is to explore the role of the IBD risk gene CCNY, encoding the Wnt signalling activator Cyclin Y, in intestinal homeostasis and wound repair.

Because Wnt signalling is essential for the maintenance of intestinal epithelial stem cells, we anticipate that CCNY mutations impair intestinal Wnt signalling and thereby reduce epithelial regeneration during colitis.

Posted in Fellowships & Grants Synopsis Reports, ECCO News, Committee News, SciCom, Volume 13, Issue 4

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