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Title: Natural killer cells and acute myeloid leukaemia
Author: Stringaris, Katherine
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Despite successful induction chemotherapy, most patients with acute myeloid leukemia (AML) will relapse. Immune surveillance by T cells or natural killer (NK) cells may play a role in preventing relapse. This thesis examines the potential of NK cells to control AML. Study 1 explored in 248 patients with haematological malignancies from the US National Institutes of Health, the genetic diversity of NK killer immunoglobulin receptor (KIR) genes in patients and their stem cell donors and their impact on outcome after stem cell transplantation (SCT) for haematological malignancy. Individuals with AML receiving SCT from donors inheriting 3 particular B-haplotype KIRs were 4 times less likely to relapse than those with donors without these favourable KIRs. Study 2 explored in samples obtained from 499 patients enrolled on UK MRC/NCRI AML trials, whether KIR genotype affects the risk of developing AML or the outcome of remission induction chemotherapy. While KIRs had no effect on the development or outcome of de novo AML, individuals with more activatory KIRs, in particular 2DS2, developed significantly less secondary AML, suggesting that activatory KIRs can protect against secondary AML. These studies support a role for NK-mediated immune surveillance in AML. Study 3 investigated the phenotype and function of AML NK cells. In 32 prospectively collected samples from AML patients undergoing remission induction chemotherapy at the Hammersmith Hospital, AML patients were found to have reduced NK activatory receptors, increased NK inhibitory receptors, and reduced cytotoxic function towards leukaemia, compared to healthy donors. These abnormalities corresponded with failure to achieve remission and can be induced in normal NK incubated with AML blasts. I conclude that KIR genetics have a limited influence on AML development and outcome but that AML itself can impair NK function, reducing the chance of achieving remission. These findings have implications for NK based immunotherapy for AML.
Supervisor: Apperley, Jane Sponsor: Leuka ; British Society for Haematology ; National Institutes of Health ; National Institute for Health Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available