dc.contributor.author | Besley, Caroline | |
dc.date.accessioned | 2017-06-26T10:31:19Z | |
dc.date.available | 2017-06-26T10:31:19Z | |
dc.date.issued | 2017-09-01 | |
dc.date.submitted | 2017-05-23T13:16:56.613Z | |
dc.identifier.citation | Besley, C. 2017. Defining the mechanisms by which lenalidomide can modulate the human T cell alloresponse to improve the outcome of allogeneic haematopoietic stem cell transplantation. Queen Mary University of London | en_US |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/24557 | |
dc.description | PhD | en_US |
dc.description.abstract | Immunomodulatory drugs (IMiDs) could enhance both direct anti-tumour and graft-versus-tumour effects after allogeneic haematopoietic stem cell transplantation (AHSCT). However, clinical experience with IMiDs after AHSCT using adult peripheral blood (APB) as a stem-cell source has been limited by graft-versus-host disease. Characterization of the mechanisms by which IMIDs modulate alloresponses of T cells and identification of differential effects on T cells from different cell sources could facilitate more effective use of these drugs in the setting of AHSCT. Using in vitro modelling, multi-parameter flow cytometry and gene expression analysis, I have determined the impact of the widely used IMiD lenalidomide on alloresponses of APB and umbilical cord blood (UCB)-derived T cells.
Lenalidomide-treatment potentiates net alloproliferation of APB-derived T cells by selectively enhancing proliferation of CD8+ T cells. These CD8+ T cells have enhanced effector memory differentiation, are enriched for polyfunctional effectors, have enhanced direct-cytotoxicity against heamatopoietic target-cells and have a distinct gene expression profile with altered expression of key immunoregulatory-genes and depletion of cellular ikaros.
Importantly, while effects on CD8+ T cells derived from UCB are similar, lenalidomide has contrasting effects on allospecific proliferation of APB and UCB-derived CD4+ T cells. While lenalidomide-treatment has no effect on alloproliferation of APB-derived CD4+ T cells, it reduces alloproliferation of UCB-derived CD4+ T cells. The reduction in UCB-derived CD4+ T cell alloproliferation is accompanied by selective expansion of CD4+CD25+FOXP3+ regulatory T cells (Treg), resulting in an overall reduction in UCB-derived T cell alloproliferation.
These findings demonstrate that lenalidomide has a differential impact on alloresponses of T cells from different cell sources; alloresponses of APB-derived T cells are increased via selective expansion of polyfunctional CD8+ effectors, while alloresponses of UCB-derived T cells are limited by expansion of tolerogenic Treg. These findings have important implications for the future use of IMiDs in the setting of AHSCT. | en_US |
dc.description.sponsorship | MRC (Clinical Research Fellowship MR/M001733/1) and Barts and The London Charity (Clinical Research Fellowship 512/1737). | en_US |
dc.language.iso | en | en_US |
dc.publisher | Queen Mary University of London | en_US |
dc.rights | The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author | |
dc.subject | Haemato-Oncology | en_US |
dc.subject | allogeneic haematopoietic stem cell transplantation | en_US |
dc.subject | Immunomodulatory drugs | en_US |
dc.title | Defining the mechanisms by which lenalidomide can modulate the human T cell alloresponse to improve the outcome of allogeneic haematopoietic stem cell transplantation | en_US |
dc.type | Thesis | en_US |