Effects of Immune response modifiers (IRMs) on the Immune system response toInjury in mice and on the developement of the two-hit response phenotype

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The immune system responds rapidly to traumatic injuries by reacting to tissue damage. Recent studies examining the effects of injury on innate and adaptive immune system phenotypes have shown that traumatic injuries induce both inflammatory and counter-inflammatory type immune responses. We believe that these changes ultimately disrupt immune system homeostasis and that it is the loss of homeostasis that predisposes trauma patients to opportunistic infections and complications. The primary objective of this project will be to use early immune response modifiers (IRMs) to help the immune system recover from injury by reducing this imbalance in immune system function and restoring immune system homeostasis. Immune response modifiers (IRMs) are broadly defined as molecules that act on immune cells to induce functional changes in the immune system by altering cellular or mediator response phenotypes. Established IRM treatments based on mTOR signal inhibition will be re-evaluated for their potential to restore immune system homeostasis after burn injury. The aim of the study therefore will be (a) to define the phenotypic changes in the immune system caused by beneficial or detrimental immune response modifier (IRM) treatments for injury in mice an (b) to study in vivo and cellular mechanisms responsible for the effects of mTOR inhibition, CpG DNA, IL-12, and IL-18 treatments on the predisposition to sepsis after injury.We hypothesize that the loss of immune system homeostasis is a central feature of trauma complications and that treatment with immune response modifier (IRM) can act early during trauma to redirect the clinical trajectory of the injury response to help restore homeostasis. Therefore, we will define the phenotypic changes in the immune system of mice caused by beneficial or detrimental immune response modifier (IRM) treatments for injury in mice using a systems immunology approach. Sepsis in mice will be induced by cecal ligation and puncture (CLP) procedure and lung infection. Multi-color flow cytometry will be used to measure immune cell subset changes in blood, spleen, and lymph nodes prepared from burn-injured male mice. Taken together, the results of these experiments will help identify the phenotypic details of how beneficial treatments with different IRMs influence immune system functions in vivo and will provide mechanistic information needed to advance potential IRM treatments to clinical testing.