MIRA · Characterizing Microbe-specific Immune Responses in the pathogenesis of Autoimmunity
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-09-01 → 2019-08-31
- EU contribution
- €173,857
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Characterizing Microbe-specific Immune Responses in the pathogenesis of Autoimmunity
Inflammatory bowel disease (IBD) comprehends a group of heterogeneous diseases characterized by chronic inflammation of the gastro-intestinal tract. The incidence of IBD is dramatically increasing in Europe and worldwide, especially in children. Therapeutics for IBD represent an unmet medical need, since a significant proportion of patients fails to respond to currently available immunotherapies. A better understanding of the immunological events that are associated with each different form of IBD is needed to pave the way to new targeted therapeutic interventions. T lymphocytes are key regulators of intestinal and systemic health. In the intestine, T lymphocytes play a dual role, i.e. defending our body against pathogens while maintaining a controlled unresponsiveness (immune tolerance) towards innocuous components of the intestinal microenvironment, such as nutrients and the commensal microbiota. It is increasingly accepted that an unbalanced immune response against the commensal microbiota – a complex consortium of bacteria that normally live symbiotically within our intestines – contributes to the initiation and/or exacerbation of IBD. Yet, little is known about the events that lead to the activation of our immune system against such beneficial bacteria. The main purpose of this proposal was to identify the mechanisms that lead to the activation of T lymphocytes against one commensal bacterium that is specifically targeted by the immune system of IBD patients. Furthermore, we aimed at understanding how those activated lymphocytes would migrate to the intestines and cause mucosal inflammation. By deeply characterizing the commensal-specific immune response, we ultimately aimed at identifying novel therapeutic targets for the treatment of IBD.
Data: CORDIS, © European Union
Project objective
Dysregulation in the balance of CD4+ T helper cell populations can severely alter susceptibility to a number of chronic inflammatory diseases, including inflammatory bowel disease (IBD). The incidence of IBD is dramatically increasing in Europe and worldwide and its therapy represents an important unmet medical need, since a significant proportion of patients fail to respond to currently available immunotherapies. Therefore, a better characterization of the immunological events underlying each form of IBD is of foremost importance. Increasing evidence points to the pivotal role of a dysregulated mucosal immune response to the intestinal microbiota in the pathogenesis of IBD. However, little is known about the mechanisms contributing to the generation of commensal-specific adaptive immune responses, and whether their differential localization can shape severity and anatomical extent of the disease. Indeed, the intestines comprise anatomically distinct regions that are exposed to different luminal antigens and this diversity eventually determines a regionalization of intestinal immune functions and microbiota-specific T cell responses. The aim of this proposal is to deeply characterize microbiota-specific T cell responses generated under different inflammatory conditions, in terms of differentiation, plasticity, heterogeneity, function and homing potential. To this aim, the proposed work will combine the use of CBir1 TCR transgenic mice, whose T cells recognize a microbial antigen that is immunodominant in IBD patients, and cutting-edge techniques such as single-cell RNA sequencing.By modelling the microbiota-specific immune response in vivo in the context of gut inflammation, I will characterize the function and homing properties of microbiota-specific T cells at the population and single-cell level, aiming at identifying new therapeutic targets for the treatment of localized forms of gut inflammation.
Original text from CORDIS.
Participants
- KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
Links
Data: CORDIS, © European Union