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

免疫系统通过对组织损伤做出反应来对创伤性损伤做出快速反应。 最近的研究检查损伤对先天性和适应性免疫系统表型的影响，表明创伤性损伤诱导炎症和抗炎类型的免疫应答。 我们认为这些变化最终会破坏免疫系统的稳态，正是这种稳态的丧失使创伤患者容易发生机会性感染和并发症。 该项目的主要目标是使用早期免疫反应调节剂（IRMs），通过减少免疫系统功能的不平衡和恢复免疫系统稳态来帮助免疫系统从损伤中恢复。免疫应答调节剂（Immune response modifiers，IRMs）被广泛地定义为作用于免疫细胞以通过改变细胞或介质应答表型来诱导免疫系统中的功能变化的分子。 将重新评估基于mTOR信号抑制的已建立的抗肿瘤治疗在烧伤后恢复免疫系统稳态的潜力。因此，本研究的目的是（a）确定由有益或有害的免疫应答调节剂（IgM）治疗小鼠损伤引起的免疫系统的表型变化，和（B）研究负责mTOR抑制、CpG DNA、IL-12，我们假设，免疫系统稳态的丧失是创伤并发症的一个中心特征，并且使用免疫应答调节剂（Immune response modifier，IL-18）治疗可以降低创伤后脓毒症的发生率。可以在创伤早期发挥作用，重新定向损伤反应的临床轨迹，以帮助恢复体内平衡。因此，我们将使用系统免疫学方法来定义由有益或有害的免疫应答调节剂（Immune response modifier，ERF）治疗小鼠损伤引起的小鼠免疫系统表型变化。小鼠败血症将通过盲肠结扎和穿孔（CLP）程序和肺部感染诱导。多色流式细胞术将用于测量从烧伤雄性小鼠制备的血液、脾脏和淋巴结中的免疫细胞亚群变化。总之，这些实验的结果将有助于确定不同IRM的有益治疗如何影响体内免疫系统功能的表型细节，并将提供将潜在的免疫治疗推进到临床测试所需的机制信息。

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.