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Title: The role of the killer immunoglobulin-like receptor in haematological malignancies and stem cell transplantation
Author: Gabriel, Ian
ISNI:       0000 0005 0732 403X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Natural killer cells (NK) cells are marrow-derived cytotoxic lymphocytes, representing 5-18% of human blood mononuclear cells. NK cells are an important component of the innate immune system in humans playing important roles in both the elimination and control of tumour metastases and leukaemia. NK activity against target cells is determined, by the net balance of the transmitted intracellular signals from both activating (pro-cytotoxic) and inhibitory (anti-cytotoxicity) cell surface receptors. One major class of such receptor is the Killer immunoglobulin-like receptors (KIRs), which were investigated in detail in this study. Using KIR genotype and HLA typing, I found that the KIR2DS1 positive genotype was an independent predictor for failure to achieve complete cytogenetic response (CCyR) and for inferior progression-free survival (PFS) in patients with chronic myeloid leukaemia in first chronic phase disease (CML-CP) treated with tyrosine kinase inhibitors. This was validated in a further 174 CML-CP patients and demonstrated therefore that KIR-HLA immunogenetics is a novel prognostic tool for patients with CML in CP. Following this finding, I hypothesised that as KIR-HLA genotype can predict for outcome in haematological malignancy, then their influence might be greatest at a time of relative NK cell predominance, such as in the immediate post transplant setting. I therefore went on to investigate and demonstrate in the malignancy multiple myeloma (MM), that KIR3DS1 positivity may identify patients at greater risk of progression after an autologous stem cell transplant, and further that there was a significant association of the KIR2DS2/DL2 genotype with acute graft-versus host disease (aGVHD) following allogeneic stem cell transplant. I finally demonstrate that the association of KIR2DS2/DL2 with GvHD is likely due to the demonstration that KIR2DS2/DL2 expressing cells have a significantly greater capacity for the production of IFN-gamma and TNF-alpha, which are directly associated with aGvHD with a relative reduction in IL-2 production which is important for regulatory T-cell development. In conclusion my data show that KIR genotype predicts both the response to targeted therapy in CML, that the role of KIR is also important in disease control during haematopoeitic reconstitution following transplant and that certain KIR molecules associate with increased incidence and severity of aGvHD and this may be mediated by the increased propensity to produce TNF-α, IFN-γ, MIP1-alpha, and MIP1-beta and a reduction in IL-2.
Supervisor: Rezvani, Katayoun; Foroni, Letizia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral