The role of nitric oxide-induced regulatory T cells in inflammation

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Numerous diseases have been found to be perpetuated by the uncontrolled actions of our own immune system. A group of regulatory immune cells have been recently discovered, which are able to modulate the immune system to avoid this. Unfortunately these cells are not able to suppress all inflammatory mechanisms leaving a dangerous gap in this balance.
A new group of regulatory cells, called NO-Tregs, have been described at the sponsoring laboratory and these cells appear to bridge the fissure left by conventional regulatory cells. NO-Tregs are capable of controlling the inflammatory response within cells detecting bacterial products, which if activated inappropriately, can lead to tissue damage. NO-Tregs are also able of suppressing a subgroup of cells whose enhanced presence has been implicated in numerous illnesses such as multiple sclerosis and asthma.
This project aims to investigate NO-Tregs further to understand the mechanisms by which these regulatory functions are achieved using both cell-based experiments as well as models of airway inflammation. Greater understanding of these mechanisms may prove vital in the future creation of targeted therapies aimed at redressing the careful balance in our immune system required in health.

Technical Summary

There is increasing evidence supporting the vital role of regulatory T cells (Tregs) in immune mediated disease. The sponsor laboratory has recently described a new subset of Foxp3 negative
Tregs (NO-Tregs) induced by nitric oxide (NO). Our pilot data show that NO-Tregs suppress the differentiation and proliferation of Th17 cells which normally escape the suppression of conventional Tregs. Th17 is a novel subset of effector T cells which mediate a range of autoimmune diseases including rheumatoid arthritis and asthma. Our pilot data also show that NO-Tregs can suppress the function of the NALP3 inflammasome, responsible for the production of IL-1? and IL-18, key pro-inflammatory cytokines implicated in numerous disease states. The present project will test the hypothesis that NO-Tregs regulate both the adaptive and the innate immune system by suppressing Th17 cell differentiation/proliferation and the inflammasome, respectively. I will determine the potential role of NO-Tregs in vivo using an ovalbumin-induced airway inflammation model. In parallel, I will perform an in depth investigation of the molecular mechanisms by which this suppression is achieved using this in vivo and relevant ex vivo systems. This project will therefore advance understanding of fundamental immunology mechanisms with considerable potential for clinical applications in numerous autoimmune conditions. The project will provide me with advanced training in cellular, molecular and in vivo immunology in inflammation, dovetailed with my clinical training in respiratory medicine.

Publications

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Gabriele L (2013) Novel allergic asthma model demonstrates ST2-dependent dendritic cell targeting by cypress pollen. in The Journal of allergy and clinical immunology

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Mirchandani AS (2015) Innate lymphoid cells in type 2 immune responses. in Archivum immunologiae et therapiae experimentalis

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Mirchandani AS (2014) Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. in Journal of immunology (Baltimore, Md. : 1950)

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Mirchandani AS (2012) Interleukin-33 and the function of innate lymphoid cells. in Trends in immunology

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Niedbala W (2011) Regulation of type 17 helper T-cell function by nitric oxide during inflammation. in Proceedings of the National Academy of Sciences of the United States of America

 
Description ATS International Trainee Travel Award 2012
Amount $2,000 (USD)
Organisation American Thoracic Society 
Sector Learned Society
Country United States
Start 05/2012 
End 06/2012
 
Description Annual Inflammatory Airway Diseases and Clinical Allergy Grant (for best abstract selected by 5 Members Association of European Respiratory Society)
Amount € 2,000 (EUR)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country European Union (EU)
Start 09/2011 
End 09/2011
 
Description Novel allergic asthma model demonstrates ST2-dependent dendritic cell targeting by cypress pollen. 
Organisation National Institute of Health
Department Department of Hematology, Oncology and Molecular Medicine
Country Italy 
Sector Public 
PI Contribution We performed key in vivo experiments on ST2 knockout mice to show the role of dendritic cells in pollen-induced allergic disease which culminated in a publication.
Collaborator Contribution They performed all the other experiments described in the paper
Impact PMID: 23608732
Start Year 2011