Myeloid Suppressor Cells in Sepsis and Trauma

描述（由申请方提供）：脓毒症与适应性免疫异常相关，使宿主继发机会性感染的风险增加。本提案的总体目标是确定髓源性抑制细胞群（MDSC）是否有助于严重脓毒症的结局和适应性免疫抑制。MDSC是具有抑制细胞活性的不成熟骨髓细胞的异质群体。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治疗途径，以改善严重脓毒症中观察到的免疫抑制。因此，提出了三个具体目标：1。确定哪些MDSC细胞亚群具有这些免疫抑制特性，以及通过何种机制（NO，活性氧）获得这些免疫抑制特性。2.确认和鉴定微生物败血症中MDSC群体扩增所需的MyD 88依赖性细胞过程，以及这些MyD 88依赖性过程是否涉及CSF超家族成员的内源性产生，以及3.确定MDSC群体对脓毒症的反应是否会调节获得性免疫反应，并可能改变继发性感染激发的结果。将在脓毒症小鼠中定量MDSC数量和功能，以及适应性免疫抑制的程度和对二次细菌攻击的敏感性。将通过流式细胞术测定MdSC数量（CD 31 + CD 11b +GR-1+），同时通过与CD 4+和CD 8+脾细胞共培养以响应抗原特异性和非特异性增殖信号，在功能上评价抑制细胞活性。在体内条件下，还将确定这些MDSC群对辅助性T细胞极化（Th 1对Th 2）的影响。最后，CLP后上述时间点的小鼠将经受继发性细菌感染（铜绿假单胞菌肺炎或李斯特菌病）以确定其易感性。因此，拟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性检查。 公共卫生相关性：脓毒症是一种与显著免疫抑制相关的危及生命的疾病。了解未成熟髓源性抑制细胞在脓毒症中的作用可能会导致新的治疗干预措施。该计划将探索脓毒症中骨髓，脾脏和淋巴结中这种细胞群大量扩增的机制，以及其对脓毒症诱导的免疫抑制的作用机制。

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.