The role of dendritic cells in Salmonella typhimurium mediated diabetes prevention in NOD mice

Lead Research Organisation: University of Cambridge
Department Name: Unlisted

Abstract

In Type 1 diabetes the immune system of an individual selectively destroys the cells in the body that secrete insulin, a hormone which is essential for maintaining glucose levels in the body. Although the development of this disease is governed by genetic factors it is clear that environmental factors additionally play a big role in determining whether Type 1 diabetes actually develops in a genetically prone individual. Among the environmental factors that might impact on diabetes development is infection. We, and others, have shown that some worm or bacterial infections actually prevent diabetes onset in a mouse model of Type 1 diabetes. By identifying the mechanisms by which infections prevent diabetes onset in this model this may lead to the development of novel therapies to prevent this autoimmune disease developing in humans.

Technical Summary

The development of autoimmune diseases such as Type 1 diabetes is governed by both genetic and environmental factors. The incidence of Type 1 diabetes is increasing in the UK at a rate of more than 4% per year. This is faster than can be accounted for by genetic change and highlights the importance of environmental influence on disease development.
The NOD mouse has provided a powerful model with which to study the role of these factors in the development of Type 1 diabetes. We have previously shown that infection of NOD mice with Salmonella enterica serovar typhimurium prevents onset of diabetes and our more recent studies highlight the importance of dendritic cells (DCs) in disease prevention. We have shown that if we isolate DCs from mice previously infected with Salmonella, we are able to prevent diabetes induction in recipient NOD mice. Our main objective is to determine how infection has altered DCs such that they mediate diabetes prevention. We propose to study DCs from previously infected or control mice investigating longterm phenotypic and functional changes following infection. In terms of functional changes we will monitor the phagocytic activity of the DCs, characterise their cytokine production and examine their ability to present antigen to islet reactive CD4+ T cells and CD8+ T cells. A more detailed investigation of DC gene expression will additionally be carried out to compare DCs from infected and control mice. Our data has indicated that DCs from infected mice are able to alter the trafficking of T cells into the pancreas and preliminary studies suggested that this may be due to alterations in chemokine and chemokine receptor expression profiles in the pancreas and pancreatic lymph nodes. We therefore propose to examine chemokine and chemokine receptor expression in these tissues in more detail using quantitative RT-PCR and immunohistochemistry. We will visualise these trafficking differences in vivo by using 2-photon microscopy in a collaborative study with Professor Paul Garside at the University of Strathclyde.

Publications

10 25 50
 
Title NOD ES 
Description embryonic stem cell line from NOD mice 
Type Of Material Cell line 
Year Produced 2009 
Provided To Others? Yes  
Impact Cells have been successfully targetted to generate novel transgenic mice. 
URL http://www.nature.com/nm/journal/v15/n7/full/nm.1996.html
 
Description Biomarkers and Type 1 diabetes 
Organisation University of Cambridge
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We supply the material from diabetes protected NOD mice for biomarker analysis.
Collaborator Contribution Dr Griffin and I have an MRC project grant to study biomarkers associated with Type 1 diabetes
Impact None so far apart from meeting abstracts.
Start Year 2009
 
Description Annual Cogress British Society for Immunology Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact This was given to an audience of 100s.

BSI Congress, LIverpool, December 2011
Parasite modulation of autoimmune diseases

Paola Zaccone,Oliver T Burton, Gabriele Schramm, Helmut Haas, Michael J Doenhoff, David W Dunne and Anne Cooke



Dr Zaccone has been asked to attend further conferences and present data.
Year(s) Of Engagement Activity 2011
URL http://www2.kenes.com/bsi2011/ScientificProgramme/Documents/BSI-WebSite-Prospectus.pdf
 
Description Cambridge International Science Summer School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact The audience comprised around 70 people who were a mix of school children and others interested in continuing education.

Some of the students asked to see the laboratories and wanted advice about how to carry out a career in science.
Year(s) Of Engagement Activity 2010,2011
URL http://www.ice.cam.ac.uk/courses/summer-schools/summer-school-programmes/science