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Role of extracellular miRNAs in T cell development, TH2 cell differentiation and TH2 cell-mediated effector function

Periodic Reporting for period 1 - miRNAs in TH2 cells (Role of extracellular miRNAs in T cell development, TH2 cell differentiation and TH2 cell-mediated effector function)

Reporting period: 2015-08-01 to 2017-07-31

Millions of Europeans suffer from allergy, a condition worryingly common among children and young adults. Although mostly manageable, some allergies can be life threatening. Standard of care is limited to the management of symptoms, and therapies aimed at curing the disease are currently absent . Allergic reactions are caused by a hyper-activated immune system. Immune cells in the body, called “T helper 2” (TH2) cells, are the coordinators of an inflammatory cascade that is responsible for many of the pathologies and symptoms associated with allergy. The aim of this project is to better understand how TH2 cells develop and cause disease, to identify novel therapies to prevent allergy.

TH2 cells secrete soluble protein mediators called “cytokines” that pull the trigger on inflammation. For example, factors secreted by TH2 cells are responsible for sensitisation to allergens like pollen, grass or house dust mite. These factors are linked to sneezing, wheezing and rashes typical of allergic reactions. They also cause hyper-secretion of mucus in the airways, particularly in allergic asthma. This project investigates a new class of secreted factors - called miRNAs - produced by TH2 cells. While this project was supported by the European Commission, we performed experiments to identify: i) which miRNAs are secreted by TH2 cells; ii) which miRNAs are transferred to other cells of the immune system; iii) what are the molecular mechanism that govern miRNA secretion; iv) what is the biological implication of secreted miRNAs in the development of allergic asthma.

As a result of this project we will publish our findings in full advancing our understanding of how the body responds to allergens, the immune system and the development of immunological diseases (see below). This project will help to expand the therapeutic window to treat different immunological disorders, from allergies to autoimmune diseases.
During the course of the project funded by the European Commission, we used different techniques to produce and isolate TH2 cells, and to study the capacity of these cells to induce allergic asthma. We used genetically modified mice to selectively remove miRNAs we hypothesis are secreted by TH2 cells, and tested their therapeutic potential.

Results overview: we so far produced results: i) screen for novel miRNAs that can potentially be transferred from TH2 cells to other cells; ii) identified a potentially novel mechanisms by which miRNAs are produced and maintained in TH2 cells; iii) produced preliminary data indicating that one particular miRNA could be responsible for the manifestation of allergic asthma. Once published, these data will help to shape future research direction, and provide novel insight on miRNAs involvement in allergic disease.
Result exploitation and dissemination: These results will help the development and production of novel therapies for the treatment and cure of different type-2 related diseases, from allergy to autoimmunity. The results produced by this study, partially supported by the European Commission, will soon be made available through scientific publications, and its content will be disseminated to the general public with the support of our lab, the publisher and the host institution. We think we provided a solid contribution on the basic understanding of T cell biology, the development of allergy and possible drug discovery.
miRNAs transfer between cells is a new, exciting mechanism that life has produced to take control of different biological phenomena. Our data suggest that transfer of miRNA may also be responsible for the development and recurrence of allergy, shifting our understanding of how the immune system works. This discovery opens up new avenues for intervention, and allows the exploration of new strategies to combat allergies. This project will provide the industry with new potential strategies for intervention, by targeting TH2 cells. Novel miRNA-based therapeutic interventions can be delivered to humans, but this promising technology requires a better understanding of the molecular mechanisms that follow miRNA transfer, and their physiological consequences. This project will go beyond the impact of sole allergic reactions, and will contribute to defeat infections and the treatment of autoimmune diseases.
extracellular miRNAs influence allergic asthma