Immune Dysfunction Following Severe Polytrauma & Major Surgery: Exploring Mechanisms & Identifying Potential Therapies

Abstract

Introduction Following polytrauma and major surgery patients experience a period of immunosuppression, which can predispose them to the development of nosocomial infections. This thesis examines how polytrauma and surgery influences T-helper (Th) cell differentiation and antigen presentation, whilst exploring how the detrimental immunomodulatory effects of these insults may be reversed. Methods Serial blood samples were drawn from two cohorts of patients at The Royal London Hospital; following severe polytrauma (n=112) or major abdominal surgery (n=119). mRNA levels of candidate cytokines and transcription factors were assayed, along with protein levels of key cytokines IL-10 and IL-6. Associations between these data, acquisition of nosocomial infection and outcome were described. As a validated surrogate of immune competence CD14+HLA-DR levels were quantified. In vitro models explored the reversibility of tissue damage induced immunosuppression and determined the role of individual circulating mediators in altering host immune function. Results A consistent up-regulation in gene expression of prototypical anti-inflammatory pathways in conjunction with features of depressed pro-inflammatory Th cell pathways was detected across both cohorts. This was accompanied by early down-regulation of CD14+HLA-DR. Gene expression changes were quantitatively associated with the subsequent acquisition of nosocomial infections. Allogeneic blood transfusion exacerbated these findingsand was independently associated with an increased risk of nosocomial infection. Culture experiments determined that postoperative decreases in antigen presentation were IL-10 dependent and reversible in the presence of Interferon-Gamma and Granulocyte Monocyte- Colony Stimulating Factor. Conclusions This thesis describes a significant host immune response immediately following significant tissue damage which is dominated by features of immune suppression. Blood transfusion appears to have a distinct, additive effect. These data identify a potential role for targeted treatment with currently licenced immune stimulants (IFN-γ and GM-CSF). In addition exploitation of the IL-10 signalling pathway may be of importance as a strategy to reduce the incidence of nosocomial infections.