Regulation of type 2 cytokine release by Peripheral Blood Cells and its relevance to asthma pathogenesis

Project Overview

In asthma the cells lining the airways, epithelial cells, can be dysregulated in their ability to handle viruses and also to form tight junctions.  There may also be other functions of epithelial cells that are defective in asthma such that the epithelial cells fail to damp down a pathogenic immune response.  We have been using an in vitro system to characterise the regulation of cytokine release by peripheral blood mononuclear cells (PBMC) and how both incubation with epithelial cells and with conditioned media from epithelial cells reduces the amount of IL-13 or IL-5 secreted by the PBMC.  We have found that asthma epithelium may be less effective at reducing this IL-13/IL-5 response.  This project will have the following aims:

1) To further characterise this IL-13 regulatory pathway to identify the cells involved and determine the nature of the inhibitory factor using biochemical or proteomic approaches. 

2) When we discover the nature of the factor(s) involved we will search whether this factor is altered during the pathogenesis of asthma.  There is an established cohort of asthma patients from which samples are available.  In addition this project will explore whether activating the epithelial cells using IL-6, IL-33, IL-1b or TSLP renders the epithelial cells unable to regulate the release of IL-13. 

3) In vivo approaches will be used such as ccsp/il13 bi-transgenic mice or LPS or IL-33 treated wildtype mice to determine the role of epithelial cell responsive and derived cytokines.  This project could lead to identification of new biomarkers for the treatment or prevention of disease or identification of factors which could be important in the regulation of asthma.  This will also enhance our basic knowledge about the pathogenesis of asthma and how different pathways work together in this chronic inflammatory disease.

Training Opportunities

The Respiratory Medicine Unit laboratory is located at the John Radcliffe Hospital where we have resources and facilities to undertake cellular and molecular immunology techniques.  The skills utilised will be tissue culture, ELISA cytokine assay, Flow cytometry and multiplex assays.  We have the ability to utilise proteomic techniques in collaboration with the Target Discovery Institute.   This project would enable students to do basic science experimental techniques as well as get involved with clinical research.  We have an ongoing programme of clinical trials so there are opportunities to learn about the process of clinical research and the operation of clinical trials.   

Theme

Immunology & Infectious Disease

Admissions

Project reference number: 976

Funding and admissions information

Supervisors

Name Department Institution Country Email
Dr Timothy Hinks MRCP Experimental Medicine Division Oxford University, John Radcliffe Hospital GBR timothy.hinks@ndm.ox.ac.uk
Professor Ian Pavord FMedSci FRCP Experimental Medicine Division Oxford University, John Radcliffe Hospital GBR ian.pavord@ndm.ox.ac.uk
Dr Timothy Powell Respiratory Medicine TDI GBR timothy.powell@ndm.ox.ac.uk

There are no publications listed for this DPhil project.