Defining the role of GMCSF in Type 2 inflammation

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences

Abstract

Building upon ongoing collaboration Andrew MacDonald's laboratory at the Manchester Collaborative Centre for Inflammation Research (MCCIR) at the University of Manchester, and GlaxoSmithKline, this project aims to elevate our fundamental understanding of specific immune mechanisms that promote or regulate inflammatory disease at mucosal barrier sites. Our emphasis will be on the role of the key cytokine GM-CSF in activation of myeloid cells during development of Type 2 inflammation caused by allergen exposure or parasitic helminth infection. Our focus will be on defining dendritic cell involvement in this process, using a combination of murine in vivo and human ex vivo and in vitro approaches. In particular, we will identify the fundamental importance of GM-CSF in influencing innate cell production of the Type 2 associated chemokines CCL17 and CCL22, and how this modulates the severity of Type 2 inflammatory disease. Since CCL17 and CCL22 bind the same receptor (CCR4), CCL22 may compensate for CCL17 in some settings, with obvious implications for development of therapeutics aiming to target CCL17 or CCL22 alone. Use of blocking reagents will allow us to temporally inhibit GM-CSF, CCL17, CCL22 or CCR4, alone or in combination, in murine in vivo and human in vitro studies. Additionally, we have access to cutting-edge animal resources to enhance this project (CCL17eGFP, CCL17-/-, CCL22-/- and CCL17/22-/-). Together, this work will: 1) discover the impact of GM-CSF on innate cell sources of CCL17 during Type 2 inflammation, and 2) enable refined assessment of GM-CSF, CCL17 and CCL22 potential as therapeutic targets for inflammatory disease.
More broadly, this collaborative project with GSK will provide novel insight into disease mechanisms to better tailor existing treatments, and support the development of new therapeutics, for inflammatory diseases of the lung, intestine and other tissues.

Publications

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