Project description
Complex intestinal lymphocyte network in inflammatory bowel disease
Inflammatory bowel disease (IBD) represents a group of intestinal disorders that cause prolonged inflammation of the digestive tract. Recent discovery and characterisation of innate lymphoid cells revealed that they play important roles in mucosal immunity in addition to antigen-specific adaptive T-cells. The EU-funded GUT-SEQ project capitalises on this research to determine the complementarity and redundancy of the two lymphocyte systems for better understanding of inflammatory diseases and the development of novel therapies. The project will employ single-cell RNA sequencing to carry out comprehensive molecular dissection of the human intestinal lymphocyte compartments in IBD using a unique collection of patient samples. Researchers will determine critical disease mechanisms, identify novel subsets of tissue-resident, innate and adaptive lymphocytes associated with inflammation, and reveal novel therapy targets and how they can be used for personalised treatment.
Objective
Inflammatory bowel disease (IBD) constitutes an increasing global health burden, yet effective treatments are lacking. Hampering rationale treatment strategies, the human intestinal immune system remains largely unexplored. I have made seminal contributions to the discovery and characterization of innate lymphoid cells (ILCs) (Nat Immunol 2011, 2013 and 2016, Immunity 2012), revealing that in addition to antigen-specific adaptive T cells, innate equivalents play important roles in mucosal immunity. Determining the complementarity and redundancy of these two lymphocyte systems, acting in concert, is important for our understanding of inflammatory diseases and the development of novel therapies. For this proposal, I am in the beneficial position of having access to unique patient samples as well as established methods for single-cell RNA-sequencing to perform an ambitious and comprehensive molecular dissection of the human intestinal lymphocyte compartments in IBD. With this approach, I will determine parallels between known, and identify novel, subsets of tissue-resident, inflammation-associated, innate and adaptive lymphocytes. Building on this unprecedented molecular characterization, we will take on some of the most pressing clinical problems in IBD by performing longitudinal assessments of intestinal lymphocytes from IBD patients on conventional and biological treatments. As only a fraction of patients respond to treatment, this approach provides a golden opportunity to unveil immunological signatures of treatment response and “drug-induced transformation” of inflammation in non-responders. Furthermore, we will unfold critical disease mechanisms and reveal novel therapy targets and how they can be used to personalize treatment. In summary, my ambitious, yet feasible, proposal combines state-of-the-art technology with access to unique patient materials. My studies are likely to advance our understanding of the complex intestinal lymphocyte network in IBD.
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Funding Scheme
ERC-STG - Starting GrantHost institution
17177 Stockholm
Sweden