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Characterizing Microbe-specific Immune Responses in the pathogenesis of Autoimmunity

Periodic Reporting for period 1 - MIRA (Characterizing Microbe-specific Immune Responses in the pathogenesis of Autoimmunity)

Reporting period: 2017-09-01 to 2019-08-31

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.
During the 2-year project period, we adopted a stepwise approach to investigate the activation, function and migration of T lymphocytes specific for commensal microbes that are relevant to human IBD. First, we set up an in vivo model for the study of T cell activation against commensal bacteria in the context of intestinal inflammation. By injecting commensal-specific lymphocytes into mice undergoing colitis and monitoring accumulation of those cells in different lymphoid organs, we identified the preferential location where the commensal-specific immune response is initiated during colitis. Next, we used different state-of-the-art experimental approaches to analyse the function of commensal-specific lymphocytes during acute and chronic colitis. Hence, we generated needed evidence for the pro-inflammatory potential of commensal-specific cells. Moreover, we observed the ability of activated commensal-specific lymphocytes to migrate to the colon mucosa in two separate models of colitis, suggesting this selective migration as a possible target for intervention in colonic IBD. Further experiments are currently investigating the molecular requirements for such migration.
Together with their migratory potential, we also demonstrated the capacity of commensal-specific cells to reshape their function over time and in different anatomical locations. We believe that this is another important node for therapeutic intervention, as we show for the first time that the commensal-specific immune response can be reshaped under specific conditions. Dissemination of this observation via project meetings and international retreats has rapidly given rise to new collaborative projects aimed at identifying strategies to actively reshape the commensal-specific immune response and restore intestinal homeostasis.
Overall, this project has allowed us to greatly improve our understanding of the processes that drive the activation, migration and function of commensal-specific lymphocytes. Knowledge produced by this action has already generated a series of new questions and, most importantly, has suggested a potential list of cellular mechanisms to be targeted in a therapeutic perspective. Further studies are already ongoing to translate such observations into novel molecular targets for therapeutic intervention.
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