Evaluation of the Inflammatory Response in Non-human Primate (NHP) Models of Poly-trauma

Abstract

Abstract Background Trauma is a leading cause of mortality, with those surviving their initial injuries remaining at risk for death due to deleterious inflammation. Preclinical investigations of immunomodulatory therapeutics are hindered by the limitations of available animal models. We sought to develop a translatable poly-trauma model in NHPs to facilitate future translational immunotherapeutic evaluation. Methods NHPs (n=24) were randomly assigned to: 60min hemorrhage shock alone(n=8) or in combination with laparotomy (n=8) ± femur fracture (n=8), resuscitation and 24hr survival. Blood was collected at baseline (BLSN), end of shock (EOS), end of resuscitation (EOR), T=360min and T=24hr; lung tissue was collected at T=24hr. Blood and tissue cytokines were quantified by a 23 plex multiplex. Results reported as mean±SEM, Statistics: Two-tailed T-Test, with p<0.05 significant. Results Circulating IL-6, IL-10, IL-15, MCP-1, TGFa and VEGF were significantly elevated in all models as early as EOS; IL-1RA, IL-15, TNFa, IL-6, IL-10, MCP-1, TGFa and IL-5 were significantly increased as early as EOS and directly correlated with injury severity. Lung tissue G-CSF, IL-1b, IL-RA, IL-6, IL-10, IL-15, IL-17A, IL-18, MCP-1, sCD40L, TGFa and VEGF were significantly elevated and directly correlated with injury severity. Conclusion Increases in cytokines identified in all models are consistent with those reported in human trauma studies. Cytokines strongly associated with injury severity score (ISS) in humans directly correlated with model severity (IL-6 and IL-10). These models have uncovered cytokine responses not characterized in poly-trauma (IL-15), demonstrating their utility in identifying novel targets for human investigation.