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Title: Role of human interleukin-17 producing T cells (Th17) and regulatory (Foxp3+) T cells in graft versus host disease (GvHD)
Author: Alsuliman, Abdullah Saleh A.
ISNI:       0000 0004 2752 7822
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Allogeneic stem cell transplantation (AHSCT) remains the only curative option for a number of patients with haematological malignancies. The interplay between a number of T cell subsets including Th1, Th2, Th17 and regulatory-T cells (Treg) has been linked to the establishment of graft-versus-leukaemia (GvL) as well as its deleterious counterpart graft-versus-host-disease (GvHD). A recent study defined a subset of memory antigen-specific CD8+T cells, with the ability to efflux cytotoxic drugs through the (ABC)-superfamily multidrug efflux complex. I hypothesized that a subset of CD4+T cells, capable of drug efflux through the MDR pump also exists. I confirmed the existence of CD4+T cells with "stem-like" properties, capable of rapidly effluxing Rhodamine123 as well as cytotoxic drugs such as daunorubicin. I confirmed that the effluxing properties of these cells are through ABCB1 and ABCC1 transporters. Similar to their CD8 counterpart, the rhodamine-effluxing subset of CD4+T cells had a memory phenotype and was enriched within the CD161+T cell compartment. Lastly, using CMV and Flu as model antigens, I showed that viral-specific memory CD4+T cells are enriched within the rhodamine-effluxing CD4+CD161+T cell population. Once I characterized these cells, I hypothesized that, through effluxing corticosteroids and other immunosuppressant drugs,CD161+CD4+ T cells may also play a role in acute GvHD. CD161+CD4+ T cells are precursors of Th17 cells. I demonstrated that, whereas Tregs are prone to apoptosis when exposed to corticosteroids, CD4+CD161+Th17 cells rapidly efflux and survive exposure to corticosteroids and other immunosuppressive drugs in vitro. Inhibition of the ABCB1 and ABCC1 with inhibitors such as vinblastine induced apoptosis of this CD4+CD161+Th17 steroid-refractory T cell subset. I observed that patients with steroid-refractory GvHD had significantly higher frequencies of CD161+CD4+ T cells compared to patients with no or steroid-responsive GvHD. I also enumerated CD161+CD4+ T cells and Foxp3+T cells in the stem cell graft and donor lymphocytes and found an association between higher CD4+CD161+ and lower Foxp3+T cells frequencies and the risk of GvHD post-transplant. These data advance our understanding of potential mechanisms of steroid-refractory GvHD and have important implications for the development of novel therapeutic approaches for the treatment of this challenging group of patients.
Supervisor: Rezvani, Katy ; Foroni, Letizia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral