Effects of Immune response modifiers (IRMs) on the Immune system response toInjury in mice and on the developement of the two-hit response phenotype
Final Report Abstract
Despite advances in emergency medicine and supportive care, morbidity and mortality after traumatic injury remain high. For several reasons, patients who initially survive trauma are at high risk for developing secondary pneumonia. While S. pneumoniae is found in healthy individuals as commensal, it can act as pathogen causing early-onset pneumonia in severely injured patients. We believe that posttraumatic changes of the immune system ultimately disrupt immune system homeostasis and render trauma patients susceptible to complications as secondary infections and sepsis. Therefore, the objective of our research was to evaluate if CpG-oligodeoxynucleotide (CpG-ODN) could act as an immune response modifier (IRM) and restore immune system homeostasis by redirecting the immune response to trauma. To study potential beneficial effects of immune response modifying drugs on the survival after trauma and early-onset pneumonia, we developed and used a two-hit mouse model of burn-injury followed by secondary S.pneumoniae lung infection one day after injury. Using this model, we found that a single treatment with a Class A CpG-ODN 2 hours after the injury significantly improved survival of mice given a secondary S. pneumoniae lung infection. We utilized a systems biology approach, applying CyTOF mass cytometry and Luminex multiplex assays to characterize the immune response after trauma and secondary S. pneumoniae lung infection at 1 day and 3 days after infection. Consistent with previous reports, we were able to show that CpG-ODN increased the early inflammatory response of innate immune cell subsets to S.pneumoniae infection after burn-injury. Furthermore, we also detected increased activation of TCRγδ cells in the lung after CpG-ODN treatment. Since it is known that TCRγδ cells play a major role in immune surveillance and regulation of the immune response in microbial-exposed epithelia such as the lung, we used a model of TCRγδ depleted mice to evaluate if beneficial effects of CpG-ODN treatment relied on the presence of TCRγδ cells. TCRγδ cells were found to be required for mediating CpG-ODN induced, beneficial effects on cytokine production and pathogen clearance after trauma and secondary infection. Thus, this report identifies TCRγδ cells as central mediators of the beneficial activity of CpG-ODN treatment. In summary, we demonstrate that early CpG-ODN treatment of burn-injured mice enhanced the response in the lung to bacterial challenge in a TCRγδ cell dependent manner. The enhanced immune response resulted in improved pathogen clearance and increased the survival rate of burn-injured mice after secondary S. pneumoniae infection.
