Myeloid Suppressor Cells in Sepsis and Trauma

败血症和创伤中的骨髓抑制细胞

基本信息

批准号：
7771716
负责人：
LYLE L MOLDAWER
金额：
$ 26.11万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7771716
关键词：
Address Adoptive Transfer Agonist Animals Antibodies Antibody Formation Antigens Area Attention Bacterial Infections Biological Biological Assay Blood Bone Marrow Burn injury CD34 gene CD4 Positive T Lymphocytes CD8B1 gene CSF1R gene CSF3 gene Cell Count Cell physiology Cell surface Cells Chimera organism Clinical Trials Coculture Techniques Communities Data Defect Dendritic Cells Depressed mood Development Disease Environment Exhibits Flow Cytometry Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor Harvest Helper-Inducer T-Lymphocyte Hematopoietic Histology Homeostasis ITGAM gene Immature Monocyte Immune Immune response Immunoglobulins Immunosuppression Immunosuppressive Agents In Vitro Infection Inflammatory Inflammatory Response Interferons Interleukin-10 Interleukin-4 Intervention Intravenous Knockout Mice Laboratories Lead Life Ligation Listeria Listeriosis Literature Lymphoid Malignant Neoplasms Measures Mediating Mediator of activation protein Mental Depression Modeling Mus Myelogenous Myeloid Cells Nomenclature Opportunistic Infections Organ Outcome PECAM1 gene Patients Phenotype Play Pneumonia Population Population Heterogeneity Predisposition Process Production Property Proteins Pseudomonas Pseudomonas Infections Pseudomonas aeruginosa Publishing Puncture procedure Reactive Oxygen Species Recombinants Regulatory T-Lymphocyte Reporting Research Risk Role Sepsis Sepsis Syndrome Shock Signal Pathway Signal Transduction Sorting - Cell Movement Spleen Splenocyte Staging Stress Suppressor-Effector T-Lymphocytes T-Cell Proliferation T-Cell Receptor T-Lymphocyte TLR4 gene Testing Therapeutic Intervention Time Trauma Tretinoin Tumor-Derived acquired immunity adaptive immunity adverse outcome c-fms Proto-Oncogenes cell type cytokine free radical oxygen granulocyte improved in vivo inhibitor/antagonist innovation kinase inhibitor knockout animal lymph nodes macrophage member microbial novel novel therapeutic intervention novel therapeutics population based prevent progenitor programs public health relevance receptor reconstitution response secondary infection septic therapeutic target translational study tumor

项目摘要

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.

描述（由申请人提供）：脓毒症与适应性免疫异常相关，使宿主面临继发性机会性感染的风险增加。该提案的总体目标是确定骨髓源性抑制细胞群 (MDSC) 是否有助于严重脓毒症中的结果和适应性免疫抑制。 MDSC 是具有抑制细胞活性的未成熟骨髓细胞的异质群体。了解这些调节细胞在脓毒症期间的作用可能有助于开发潜在的新型治疗途径，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，以及通过什么机制（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 群体扩张所需的 MyD88 依赖性细胞过程，以及这些 MyD88 依赖性细胞过程是否涉及 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可调节获得性免疫反应，并可以改变继发性感染挑战的结果。脓毒症小鼠的 MDSC 数量和功能都将被定量，适应性免疫抑制的程度和对继发细菌攻击的易感性也将被定量。 MdSC 数量 (CD31+CD11b+GR-1+) 将通过流式细胞术测定，而抑制细胞活性将通过与 CD4+ 和 CD8+ 脾细胞共培养响应抗原特异性和非特异性增殖信号来进行功能评估。在体内条件下，还将确定这些 MDSC 群体对 T 辅助细胞极化（Th1 与 Th2）的影响。最后，CLP后上述时间点的小鼠将遭受继发性细菌感染（铜绿假单胞菌肺炎或李斯特菌病）以确定其易感性。因此，拟议的研究代表了对新型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：脓毒症是一种与严重免疫抑制相关的危及生命的疾病。了解未成熟的骨髓源性抑制细胞在脓毒症中所起的作用可能会导致新的治疗干预措施。该项目将探讨脓毒症中该细胞群在骨髓、脾脏和淋巴结中大规模扩张的机制，以及其对脓毒症诱导的免疫抑制的作用机制。