Myeloid Suppressor Cells in Sepsis and Trauma

描述（由申请人提供）：脓毒症仍然是我们重症监护室死亡的主要原因，也是创伤和手术干预后晚期器官损伤的最常见原因。尽管支持性治疗有所改善，但严重脓毒症和器官衰竭的死亡率仅略有改善。在该奖项的初始资助期间，我们观察到一种新的未成熟骨髓细胞群体，表型类似于晚期癌症中描述的髓源性抑制细胞（MDSC），在严重脓毒症中，响应于烧伤和感染，以及暴露于特定TLR配体后急剧扩增。最初，我们假设这些细胞在脓毒症中发挥的作用与它们在晚期癌症中发挥的作用相当：抑制适应性免疫。事实上，已经积累的数据表明，MDSC的这种扩增实际上可能不是对脓毒症宿主总体有害的，而是旨在支持先天免疫的对严重脓毒症的有益应答的一部分。我们的总体假设是，MDSC的扩增通过在适应性免疫抑制和APC功能降低的情况下维持先天免疫和免疫监视在脓毒症中起重要作用。三个具体目标是：（1）确定MDSC在急性细菌感染中诱导抗微生物应答的细胞机制，包括活性氧和氮物质的产生。(2)为了确定MDSC在多微生物脓毒症中的扩增是否是维持先天免疫功能所需的，并且可以补偿导致对继发性感染的易感性和/或死亡率增加的适应性免疫抑制，以及（3）为了检查MDSC群体的类似扩增是否发生在人脓毒症或严重创伤中，如通过它们在循环中的出现所记录的，以及淋巴和网状内皮系统的器官/组织中。该计划将导致更好地了解发生在败血症和创伤中的MDSC扩张。此外，这项工作将阐明MDSC在严重脓毒症中是否发挥有益或病理作用（或两者兼而有之），以及治疗工作是否应该以抑制或扩大其作用为目标。最后，这些研究将最终解决MDSC扩增是否也发生在人类败血症和创伤中，并与炎症的严重程度相关。

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.