GutILC3 · Cell-cell interactions critical to ILC3 function in the human gut
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-04-01 → 2017-03-31
- EU contribution
- €173,857
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Cell-cell interactions critical to ILC3 function in the human gut
The overall goal of the GutILC3 project was to advance our understanding of group 3 innate lymphoid cells (ILC3) function in inflammatory bowel disease (IBD). The exact etiology of IBD is unknown, however it is considered to result from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Currently, only subgroups of patients benefit from existing therapies. The two major forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC), both conferring a dramatically increased risk for development of colorectal cancer (CRC). These intestinal diseases constitute a significant economic and health burden in Europe. In recent years, it has become clear that the inflammatory axis of IL-23–IL-17/IL-22 cytokines plays a crucial role in the intestinal mucosal inflammation. The recently described ILCs have been reported to be key players in mucosal homeostasis and inflammation. The IL-23- and IL-1β-responsive ILC3 produce IL-17 and IL-22 cytokines. Strikingly, NKp44+ ILC3 are crucial in maintaining gut homeostasis by secreting IL-22, while the IL-17-producing NKp44- ILC3 are present in human IBD and cause inflammation in a mouse model of colitis. There is an urgent need for novel therapeutic strategies in order to improve outcomes of IBD. The GutILC3 project made conceptual advancements in targeting intestinal ILC3 activity under inflammatory condition and investigated the functional heterogeneity of the various ILC3 subpopulations. Outcomes of the project will impact the European society by proposing measures for new therapeutic targets in intestinal immune-pathologies like IBD in humans. Specific objectives of GutILC3 are to: investigate cellular function of human ILC3 derived from tonsils and gut pinpoint crucial molecules or processes for targeting ILC3 function interrogate the phenotypic and functional heterogeneity of human ILC3 subsets set a base for novel therapeutic approaches in the treatment of IBD by directly targeting ILC3 activity
Data: CORDIS, © European Union
Project objective
Inflammatory bowel disease (IBD), conferring a dramatically increased risk for development of colorectal cancer (CRC), results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. However, the exact etiology of IBD is unknown. Building up on high impact papers from the host group reporting on the recently discovered innate lymphoid cells (ILCs) as key players in mucosal inflammation, I now aim to unravel the role for ILCs in IBD and CRC. Interestingly, while the IL-22 producing ILC3 seem to be crucial in maintaining intestinal homeostasis, the IL-17 and IFN-gamma-producing ILCs can cause inflammation in a mouse model of colitis and are present in human IBD. Furthermore, ILCs were recently described to be involved in modulating immune responses, by interacting with CD4+ T cells and mononuclear phagocytes in the mouse intestine. I aim to identify critical pathways in the crosstalk of ILC3 with other immune cells in the human intestine. The ultimate purpose is to assess how these interactions affect immune homeostasis and disease progression in IBD and CRC. We will pinpoint crucial interaction molecules and cellular processes that can be used for monitoring current therapies as well as finding new therapy targets for IBD and CRC.This truly translational proposal utilizes, in an optimal manner, unique state-of-the-art techniques and patient materials to provide novel insights into the etiology of IBD and CRC. The excellent track record of the hosting group, the highly suitable infrastructure provided by the host institution and my own extensive research experience ensures a high degree of feasibility. Furthermore, this project provides excellent training opportunities, skill advancement possibilities and career prospects for me and its results are expected to have a direct impact on the European society.
Original text from CORDIS.
Participants
- KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
Links
Data: CORDIS, © European Union