Myeloid Suppressor Cells in Sepsis and Trauma

描述(由申请人提供)：败血症与适应性免疫异常有关，这种异常使宿主面临继发性机会性感染的风险增加。这项建议的总体目标是确定髓系来源的抑制细胞群(MDSC)是否有助于严重脓毒症的预后和适应性免疫抑制。骨髓间充质干细胞是具有抑制细胞活性的未成熟髓系细胞的异质性群体。了解这些调节细胞在脓毒症中的作用可能有助于开发潜在的新的治疗途径来改善在严重脓毒症中观察到的免疫抑制。因此，提出了三个具体的目标：1.确定哪些MDSC亚群具有这些免疫抑制特性，以及这些免疫抑制特性是通过什么机制(S)(NO，活性氧)获得的。2.确认和鉴定在微生物脓毒症中MDSC群体扩张所需的MyD88依赖的细胞过程，以及这些MyD88依赖的过程是否涉及CSF超家族成员的内源性产生，以及3.确定脓毒症反应中MDSC群体的变化是否调节获得性免疫反应，并可能改变继发性感染挑战的结果。败血症小鼠的MDSC数量和功能将被量化，适应性免疫抑制的程度和对二次细菌挑战的敏感性也将被量化。MDSC的数量(CD31+CD11b+GR-1+)将通过流式细胞仪检测，而抑制细胞的活性将通过与CD4+和CD8+脾细胞共同培养来评估其对抗原特异性和非特异性增殖信号的反应。在体内条件下，这些MDSC群体对辅助性T细胞极化(Th1与Th2)的影响也将被确定。最后，在CLP后的上述时间点，小鼠将受到继发性细菌感染(铜绿假单胞菌肺炎，或李斯特菌病)，以确定它们的易感性。因此，建议的研究代表了一种新的抑制细胞群作为脓毒症期间免疫抑制的潜在机制的创新检查。 公共卫生相关性：败血症是一种危及生命的疾病，与显著的免疫抑制有关。了解未成熟的髓系来源的抑制细胞在脓毒症中所起的作用可能导致新的治疗干预措施。本项目将探索导致脓毒症患者骨髓、脾和淋巴结中这种细胞群大量扩张的机制，以及其在脓毒症诱导的免疫抑制中的作用机制。

DESCRIPTION (provided by applicant): Sepsis is associated with aberrations in adaptive immunity that place the host at increased risk of secondary opportunistic infections. The overall goal of this proposal is to determine whether myeloid-derived suppressor cell populations (MDSC) contribute to outcome and the adaptive immune suppression seen in severe sepsis. MDSCs are a heterogeneous population of immature myeloid cells with suppressor cell activities. Understanding how these regulatory cells act during sepsis may permit the development of potential novel therapeutic avenues to ameliorate the immune suppression observed in severe sepsis. Therefore, three specific aims are proposed: 1. To determine which MDSC cell subpopulations possess these immunosuppressive properties, and through what mechanism(s) (NO, reactive oxygen species) are these immunosuppressive properties obtained. 2. To confirm and identify the MyD88 dependent cell processes that are required for the expansion of the MDSC populations in microbial sepsis, and whether these MyD88 dependent processes involve endogenous production of members of the CSF superfamily, and 3. To determine whether alterations in the MDSC population in response to sepsis modulates the acquired immune response, and can alter outcome to a secondary infectious challenge. Both MDSC numbers and function will be quantitated in septic mice, as will the degree of adaptive immunosuppression and susceptibility to a secondary bacterial challenge. MdSC numbers (CD31+CD11b+GR-1+) will be determined by flow cytometry, while suppressor cell activity will be evaluated functionally by co-culture with CD4+ and CD8+ splenocytes in response to antigen specific and nonspecific proliferative signals. Under in vivo conditions, the effect of these MDSC populations on T helper cell polarization (Th1 vs Th2) will also be determined. Finally, mice at the above time points post-CLP will be subjected to a secondary bacterial infection (Pseudomonas aeruginosa pneumonia, or Listeriosis) to determine their susceptibility. Thus, the proposed studies represent an innovative examination of a novel suppressor cell population as a potential mechanism for immune suppression during sepsis. PUBLIC HEALTH RELEVANCE: Sepsis is a life-threatening disease associated with significant immune suppression. Understanding the role that immature myeloid derived suppressor cells play in sepsis could lead to new therapeutic interventions. This program will explore the mechanisms responsible for the massive expansion of this cell population in the bone marrow, spleen and lymph nodes in sepsis, and the mechanisms behind its contribution to sepsis induced immune suppression.