Medicine (Austin & Northern Health) - Theses
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ItemThe utility of immune function monitoring in predicting clinical outcomes in cirrhosis and following liver transplantation( 2015)Background: Transplantation is a life-saving procedure offered to thousands of people around the world each year. In most cases, lifelong suppression of the recipient’s immune system is required to prevent allorecognition and organ rejection. However, immunosuppressive medications have significant side effects that are now responsible for much of the post-transplant morbidity and mortality. Balancing the risks of over and under immunosuppression is key to patient management, but without an objective marker of immune function, clinical events remain common. QuantiFERON-Monitor (QFM) is a net immune function biomarker that measures IFNγ after stimulation of whole blood with an innate and adaptive immune stimulant. It is potentially accessible as it is based on the same laboratory platform as the readily available QuantiFERON-gold assay. The studies within this thesis represent the first translational clinical studies evaluating this assay. Methods: A cross-sectional pilot study compared QFM in healthy controls with patients before and after liver transplantation. Subsequent studies focused on immune function biomarkers and correlation with clinical events both before and after transplantation. In a cirrhotic transplant-waitlisted population, the QFM assay was performed and patients prospectively monitored for infection prior to transplant. This was followed by a prospective observational post-transplant cohort study in which QFM was taken longitudinally to assess for clinical events including infection and rejection based on pre-defined criteria. The same cohort was monitored for cytomegalovirus (CMV) reactivation with a CMV-specific T-cell assay, to evaluate the potential for more specialised immune monitoring. A small subgroup of controls and rejectors were compared for pre-transplant cytokine production using an enhanced sensitivity bead array and flow cytometry. Results: The pilot study confirmed that QFM could discriminate between populations known to be immunosuppressed. Compared with healthy controls, lower QFM was seen in patients following transplantation when on immunosuppression. QFM did not vary by age, gender or disease aetiology. In the cohort of cirrhotic patients, low QFM was associated with the risk of infection prior to transplant. This risk was also demonstrated after transplantation, where a low QFM at one week was significantly associated with risk of infection, but not rejection. Conversely, a high week 1 QFM was significantly associated with rejection, but not infection. Based on the selected optimal cut-offs, approximately 70% of all transplant patients were identified as being over- or under-suppressed. The risk of post-transplant rejection was further heightened in patients who had lower pre-transplant baseline pro-inflammatory cytokine production. QFM was not associated with risk of CMV reactivation. However, a CMV-specific immune function assay was significantly associated with CMV in patients inappropriately classified as low-risk based on current standard of care. Conclusions: Without an objective marker of immune function, clinical events remain exceedingly common following liver transplantation. The studies within this thesis represent the first translational studies involving QFM - a net immune function biomarker which benefits from being accessible, rapid and comprising both innate and adaptive immune stimulants. Future individualisation and optimisation of immunosuppression based on immune monitoring could fundamentally alter the way patients are monitored and treated following transplantation.