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Title: The effect of acute graft-versus-host disease upon the peripheral T cell niche
Author: Evans, Pamela
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Relapsed disease and infection continue to be the leading causes of treatment failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pathophysiology, common to both, is impaired donor T cell immune reconstitution and/or T cell exhaustion. Therapeutic strategies aimed at improving donor T cell immune reconstitution and preventing T cell exhaustion are required in order to improve patient outcomes. The research presented provides evidence that acute graft-versus-host-disease (aGVHD) impairs T cell recovery and function by damaging the stromal architecture of secondary lymphoid organs. Radio-resistant host non-haematopoietic antigen presenting cells (APCs) are emerging as key players in dictating tissue-specific cytotoxic T lymphocyte (CTL) responses and initiating aGVHD. The fibroblastic reticular cell (FRC) is a subset that plays a central role in every stage of the T cell life cycle in the periphery and is necessary for the generation of protective anti-pathogen immunity. Normally, these cells proliferate and repair the peripheral lymph node following viral damage or hypoxia, by initiating a ‘reorganisational programme’ through interaction with lymphoid tissue inducer (LTi)-like cells, in a mechanism akin to that which occurs during embryogenesis. I show that both the FRC and LTi-like cell populations are targeted by the allogeneic T cell response in aGVHD. Disruption of the FRC-LTi axis results in profound damage to the lymph node structure and persistent hypoplasia of peripheral T cell niches. FRCs are targeted by naïve donor T cells in a CD8+ T cell-dependent model of aGVHD, through a mechanism that requires cognate interactions between FRCs and T cells. In contrast to viral infection, lymph nodes in aGVHD are unable to mount a reorganisational programme involving LTi-like cell influx and proliferation. Sustained damage to the FRC network impairs T cell homing to lymph nodes, T cell survival and the capacity to mount a response to 3rd party antigen. These data indicate that future research should focus upon efforts to protect the FRC-LTi axis following transplantation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available