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Investigating the function of natural killer cells during immunological responses following human lung transplantation
thesisposted on 16.02.2017, 05:26 by Meehan, Aislin
In solid organ transplantation, ongoing allograft inflammation and alloreactivity is a recognised cause leading to chronic rejection and poor long term outcomes. To date, the role of Natural Killer (NK) cells in determining outcomes following lung transplantation, an established treatment for patients with advanced end stage lung disease, is not confirmed. NK cells are a population of innate immune cells that recognise virus-infected and malignant tumour cells but in addition can detect foreign proteins on transplanted tissue and so potentially exacerbate an immune response against the transplanted organ. This study in lung transplantation is unique in its examination of the role of NK cells in the post-transplant immune processes by assessing longitudinal changes in phenotype, function and potential alloreactivity. In addition the effects of the transplant immunosuppression drug regimen on the function of immune cells was observed, as well as analysis of cellular activation changes at the molecular level as a result of graft rejection and viral infections. Finally, the alloreactive potential of NK cells were assessed in response to HLA-mismatched donor cells as well as the association of NK cell KIR genotype and KIR-ligand mismatches to clinical outcomes after transplantation. A regulatory role for NK cells in the setting of lung transplantation is a much more likely scenario as it was shown that KIR/KIR-ligand mismatches were in fact associated with protection against acute rejection and protection against the development of BOS, and may instead reflect NK cell control of CMV infection in the lung allograft. The study cohort comprised 73 patients who had undergone lung transplantation at The Alfred Hospital and received ongoing routine clinical assessment. Monitoring the dynamics of NK cells can improve our understanding of their contribution to long term outcomes in lung transplant patients and may be used as a potential diagnostic marker for modulation of post-transplant medical intervention strategies including immunosuppression and/or antiviral prophylaxis; findings that may be extended into other solid organ transplant settings.