Characterisation of the immune profile and investigation of transfusion-related modulation of monocyte and dendritic cell function in cardiac surgery patients

Abstract

The transfusion of blood products such as packed red blood cells (PRBC) and platelet concentrates (PC) can be used to treat patients with haematological disorders, during surgery and in the event of severe trauma. Despite the therapeutic benefits, there is evidence that transfusion modulates the recipient immune response which has been associated with increased rates of adverse outcomes including infection and mortality. Coronary artery bypass grafting (CABG) is a complex procedure which triggers a systemic inflammatory response hypothesised to be a result of exposing patient blood to the extracorporeal circuitry associated with bypass. CABG patients are a relatively homogenous study population, which makes them suitable for the investigation of transfusion-associated immunomodulation. The underlying mechanisms of transfusion-associated immune modulation are not well characterised and understanding of the role dendritic cells (DC) and monocyte pay in mediating CABG and/or transfusion outcomes is limited. DC and monocytes play a central role by linking the innate and adaptive immune response, and dysfunction of these cells may also contribute to adverse outcomes. To improve our current understanding of modulation of the immune profile in CABG patients, and the impact of transfusion, I first assessed the immune profile in CABG patients and then I assessed the impact of transfusion in this patient group. This study demonstrates that CABG significantly modulates the patient immune profile. In addition, this study provides evidence that DC and monocytes from CABG patients were immunoparalysed as they failed to respond to secondary insult. This study also demonstrates that transfusion results in differential modulation of the immune profile in CABG patients. It has been reported that patients transfused in the ICU setting are at an increased risk of adverse outcomes such as transfusion-related acute lung injury (TRALI) driven by the presence of underlying inflammation. To assess whether underlying inflammation impacts on transfusion outcomes, I used an in-vitro whole blood culture transfusion model to assess whether changes in the DC and monocyte cytokine profile following exposure to blood products (PC or PRBC) was dependent on the level of underlying inflammation. Surprisingly, the blood products modulated the monocyte and DC specific response to a greater degree when there was less inflammation present. With the comprehensive assessment of the immune profile in CABG patients and assessment of the impact of transfusion in these patients, together with an in-vitro transfusion model to assess the impact of underlying inflammation, I have improved our current understanding of cardiac and transfusion immunobiology. In addition the immunoassays developed during this PhD can be used in other clinical settings to assess the immune profile and study transfusion-related immune modulation in other patient groups (e.g. orthopaedic patients).