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Characterising the plasticity of cutaneous myeloid cells in graft-versus-host disease

West, Heather Carol; (2019) Characterising the plasticity of cutaneous myeloid cells in graft-versus-host disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The skin is an important barrier to the external environment. Within the skin, immune cells interact to maintain a healthy protective environment in the presence of daily challenges. This requires the induction of tolerance to innocuous insults, but activation of adaptive immunity upon infection with pathogens. Within healthy skin, myeloid cells such as monocytes, macrophages, dendritic cells and Langerhans cells (LC) cooperate to maintain this balance. However, we know little about how disease may impact on these dynamic cell populations and their control of skin immunity. Haematopoietic stem cell transplantation is a curative treatment for some blood cancers. However, the beneficial anti-tumour effect is often associated with the pathophysiology of graft-versus-host disease (GVHD). This thesis is focused on understanding how the skin myeloid compartment is altered after GVHD, and the consequences of these changes on skin immunity. We have used a murine model of sub-lethal GVHD to investigate the developmental and functional impact of skin pathology on different myeloid cell populations. We have characterised the immune environment of the skin during and after GVHD and identified lasting changes to the myeloid compartment. In particular, pathology resulted in the recruitment of blood monocytes with the plasticity to differentiate into different cell types in the skin environment. Alterations to dermal myeloid cells led to defects in cutaneous immunity, including a breakdown in peripheral tolerance and protective barrier immunity. We demonstrated a profound loss of regulatory T cell function in situ and identified monocyte-derived IL-6 as a potential mediator of loss of function. We have further utilised transcriptional analyses with a reductionist in vitro culture model to infer information about myeloid cell differentiation during GVHD. The approach has identified proliferation of myeloid precursors as a critical and unreported step in LC differentiation, and highlighted the importance of interleukin (IL)-34 in the generation of a persistent LC network following injury. Together, this work has demonstrated the plasticity of myeloid cells within the skin after disease and the potential long-term consequences for skin immunity in patients who have recovered from GVHD.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Characterising the plasticity of cutaneous myeloid cells in graft-versus-host disease
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10068435
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