Myeloid Suppressor Cells in Sepsis and Trauma

描述(申请人提供)：败血症仍然是我们重症监护病房死亡的主要原因，也是创伤和外科干预后晚期器官损伤的最常见原因。尽管支持性护理有所改善，但严重脓毒症和器官衰竭的死亡率仅略有改善。在该奖项的最初资助期间，我们观察到一种新的未成熟髓系细胞群体，表型类似于晚期癌症中描述的髓系衍生抑制细胞(MDSCs)，在严重脓毒症中，对烧伤和感染的反应，以及暴露于特定的TLR配体后，显著扩大。最初，我们推测这些细胞在脓毒症中发挥的作用与它们在晚期癌症中所起的作用相当：抑制获得性免疫。事实上，已经积累的数据表明，MDSCs的这种扩张实际上可能并不是对脓毒症宿主的损害，而是旨在支持先天免疫的严重脓毒症的有益反应的一部分。我们的主要假设是，在获得性免疫抑制和APC功能降低的情况下，MDSCs的扩张通过维持天然免疫和免疫监视在脓毒症中发挥重要作用。这三个具体目标是：(1)确定MDSCs在急性细菌感染中诱导抗微生物反应的细胞机制，包括产生活性氧和氮物种。(2)确定MDSC在多菌败血症中的扩增是否是维持先天免疫功能所必需的，并且是否能够补偿导致继发感染易感性和/或死亡率增加的获得性免疫抑制；以及(3)根据MDSC在血液循环中的出现以及淋巴和网状内皮系统的器官/组织中的表现，检测MDSC在人类败血症或严重创伤中是否发生类似的扩增。这项计划将使我们更好地了解脓毒症和创伤时MDSC的扩张。此外，这项工作将阐明MDSC在严重脓毒症中是有益的还是病理的作用(或两者兼而有之)，以及治疗努力应该以抑制或扩大它们的作用为目标(S)。最后，这些研究将最终确定MDSC的扩张是否也发生在人类脓毒症和创伤中，并与炎症的严重程度有关。

DESCRIPTION (provided by applicant): Sepsis remains the leading cause of mortality in our intensive care units, and is the most common cause of late organ injury after trauma and surgical intervention. Despite improved supportive care, mortality from severe sepsis and organ failure has only modestly improved. During the initial funding period of this award, we observed that a novel population of immature myeloid cells, phenotypically similar to the myeloid derived suppressor cells (MDSCs) described in advanced cancer, expand dramatically in severe sepsis, in response to burns and infection, and after exposure to specific TLR ligands. Initially, we presumed that these cells played a comparable role in sepsis to the role they play in advanced cancer: to suppress adaptive immunity. In fact, data have accumulated that this expansion of MDSCs may in fact, not be summarily detrimental to the septic host, but rather part of the beneficial response to severe sepsis aimed at supporting innate immunity. Our overarching hypothesis is that expansion of MDSCs plays an essential role in sepsis by sustaining innate immunity and immune surveillance in the face of adaptive immune suppression and reduced APC function. The three specific aims are to: (1) To determine the cellular mechanisms by which MDSCs induce an anti-microbial response in acute bacterial infections, including the production of reactive oxygen and nitrogen species. (2) To determine whether the expansion of MDSCs in polymicrobial sepsis is required for the maintenance of innate immune function, and can compensate for the adaptive immune suppression that leads to increased susceptibility and/or mortality to secondary infections, and (3) To examine whether a similar expansion of MDSC populations occurs in human sepsis or severe trauma, as documented by their appearance in the circulation, and in organs/tissues of the lymphoid and reticuloendothelial systems. This program will lead to a better understanding of the MDSC expansion that occurs in sepsis and trauma. Further, this work will elucidate whether MDSCs play a beneficial or pathologic role (or both) in severe sepsis, and whether therapeutic efforts should be targeted at either suppressing or expanding their role(s). Finally, these studies will lead to a final resolutin whether MDSC expansion also occurs in human sepsis and trauma and is associated with the severity of the inflammation.