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Role of Mononuclear Leukocytes in Immunity

单核白细胞在免疫中的作用

基本信息

批准号：
7846622
负责人：
SAMUEL CHARLES SILVERSTEIN
金额：
$ 6.65万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2011-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846622
关键词：
3-Dimensional Acyl Carrier Protein Acylation Adhesions Adult Age Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Antibiotics Apolipoprotein E Apolipoproteins Astrocytes Attention Bacteria Bacterial Infections Beds Behavior Biocompatible Materials Brain CD36 gene Cell Adhesion Cells Characteristics Chemotactic Factors Chemotaxis Collagen Cytoplasm Defect Deposition Dermal Development Drug resistance in tuberculosis Drug-sensitive Emigrations Endocytosis Endothelial Cells Environment Equation Escherichia coli Fatty Acids Fibrin Funding Gel Gemfibrozil Genotype Gram-Negative Bacteria Grant Growth Host Defense Hour Human Immune Immunity In Vitro Integrins Invaded Legionella Legionella pneumophila Leukocyte Chemotaxis Leukocytes Leukotriene B4 Lipoproteins Literature Lymphocyte Manuscripts Measures Mediating Microbial Biofilms Microglia Modeling Mononuclear Mononuclear Leukocytes Multi-Drug Resistance Mus Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Natural Immunity Neonatal Newborn Infant Pan Genus Pathogenesis Patients Pertussis Toxin Phagocytes Phagocytosis Pharmaceutical Preparations Preparation Production Progress Reports Property Proteins Publications Published Comment Reactive Oxygen Species Regulation Reporting Research Research Project Grants Risk Factors Role SR-A proteins SR-B proteins SR-BI receptor Sepsis Serum Signal Transduction Site Staining method Stains Surface Suspension substance Suspensions System Testing Time Tissues Tuberculosis Vacuole Virulence Factors apolipoprotein E-4 axenic culture bactericide cancer cell chemokine cytotoxic formyl peptide glycation in vivo killings macrophage migration monocyte neutrophil novel oxidized low density lipoprotein receptor receptor expression scavenger receptor success tissue processing tumor

项目摘要

DESCRIPTION (provided by applicant): We have used three-dimensional fibrin and collagen I gels to compare neutrophil (PMN) bactericidal activity in tissue-like environments vs. stirred suspensions and discovered that a critical PMN concentration (CNC) is required to block the growth of bacteria in fibrin and collagen gels and in stirred suspensions. The concept that a critical leukocyte concentration is required to carry out specific immune effector functions is both novel and important. It unifies a large body of literature on host defense against bacterial infections, and provides a conceptual framework for assessing quantitatively the concentration of any class or type of immune cell that must be delivered to a tissue to execute a specific function. We have derived an equation that enables us to calculate the CNC for all bacterial concentrations under all experimental conditions so far tested. Using it we found the CNC in suspension (approximately 4 x 105 PMN/ml), is almost identical to that known to predispose neutropenic humans to sepsis, while that in fibrin gels is 2.5 - 10-fold higher (e.g., 1-4 x 106PMN/ml). Using these gels we have extended our previous observation that specific matrix proteins (e.g., fibrin) and chemoattractants (e.g., fMLP) block PMN migration by showing that in the presence of fibrin, fMLP blocks PMN bactericidal activity. Moreover, we discovered that PMN genetically deficient in a2-integrins phagocytose and kill S.epidermidis as efficiently as wild-type PMN in fibrin gels. We also have discovered that contrary to conventional wisdom, PMN have the capacity to invade and kill >98% of S. epidermidis in mature (5-day old) biofilms. We seek continued support to extend these studies, and to identify mechanisms that regulate emigration of PMN and monocytes from the blood into tissues, processes central to limiting tissue damage, and to delivering sufficient PMN and monocytes to eradicate planktonic and biofilm bacteria, and cytotoxic lymphocytes to kill cancer cells. This application has three Specific Aims. Aim #1. To measure the critical concentration of monocytes for killing S. epidermidis and E. coli in fibrin and collagen I gels in vitro, and the critical concentrations of PMN and of monocytes for killing of S. epidermidis and E.coli in vivo, and to identify the mechanisms that signal cessation of entry of PMN and of monocytes into dermal sites of bacterial infection. Aim #2. To identify the immunological mechanisms that impede PMN and monocyte killing of biomaterials-associated S. epidermidis biofilms. Aim #3. To determine whether the concept of a critical leukocyte concentration also applies to the tumoricidal activities of cytotoxic lymphocytes and monocytes. In other words, must cytotoxic lymphocytes reach a critical concentration within a tumor bed to effect a reduction in tumor mass?

描述（由申请人提供）：我们使用三维纤维蛋白和胶原蛋白I凝胶比较了中性粒细胞（PMN）在类组织环境中的杀菌活性与搅拌悬浮液的对比，发现需要一个临界PMN浓度（CNC）来阻止纤维蛋白和胶原蛋白凝胶以及搅拌悬浮液中的细菌生长。执行特定免疫效应功能需要临界白细胞浓度这一概念既新颖又重要。它整合了大量关于宿主防御细菌感染的文献，并提供了一个概念性框架，用于定量评估任何类别或类型的免疫细胞的浓度，这些免疫细胞必须被运送到组织中以执行特定功能。我们推导了一个方程，使我们能够计算到目前为止测试的所有实验条件下所有细菌浓度的CNC。使用它，我们发现悬浮液中的CNC（约4 × 105 PMN/ml）几乎与已知的使嗜中性粒细胞减少的人易患败血症的CNC相同，而纤维蛋白凝胶中的CNC高2.5 - 10倍（例如，1-4 × 106PMN/ml）。使用这些凝胶，我们扩展了我们之前的观察，即特定的基质蛋白（如纤维蛋白）和化学引诱剂（如fMLP）通过表明在纤维蛋白存在的情况下，fMLP阻断PMN的杀菌活性来阻止PMN的迁移。此外，我们发现在纤维蛋白凝胶中，PMN基因缺乏a2整合素吞噬和杀死表皮葡萄球菌的效率与野生型PMN一样高。我们还发现，与传统观点相反，PMN具有入侵和杀死成熟（5天）生物膜中约98%的表皮葡萄球菌的能力。我们寻求持续的支持来扩展这些研究，并确定调节PMN和单核细胞从血液向组织迁移的机制，限制组织损伤的核心过程，并提供足够的PMN和单核细胞来根除浮游和生物膜细菌，以及细胞毒性淋巴细胞来杀死癌细胞。此应用程序有三个特定目的。目标# 1。测定体外纤维蛋白和I型胶原凝胶中杀死表皮葡萄球菌和大肠杆菌的单核细胞临界浓度，以及体内杀死表皮葡萄球菌和大肠杆菌的PMN和单核细胞的临界浓度，并确定PMN和单核细胞停止进入细菌感染皮肤部位的信号机制。目标# 2。目的探讨表皮葡萄球菌生物材料相关生物膜中PMN和单核细胞杀伤的免疫学机制。目标# 3。确定临界白细胞浓度的概念是否也适用于细胞毒性淋巴细胞和单核细胞的杀肿瘤活性。换句话说，细胞毒性淋巴细胞必须达到肿瘤床内的临界浓度才能实现肿瘤质量的减少？

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mouse peritoneal macrophages plated on mannan- and horseradish peroxidase-coated substrates lose the ability to phagocytose by their Fc receptors.

铺在甘露聚糖和辣根过氧化物酶包被基质上的小鼠腹膜巨噬细胞失去了 Fc 受体吞噬的能力。

DOI：
发表时间：
1985
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Sung,SS;Nelson,RS;Silverstein,SC
通讯作者：
Silverstein,SC

Extracellular ATP4- promotes cation fluxes in the J774 mouse macrophage cell line.

细胞外 ATP4- 促进 J774 小鼠巨噬细胞系中的阳离子通量。

DOI：
发表时间：
1987
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Steinberg,TH;Silverstein,SC
通讯作者：
Silverstein,SC

Ca(2+)-independent F-actin assembly and disassembly during Fc receptor-mediated phagocytosis in mouse macrophages.

DOI：
10.1083/jcb.113.4.757
发表时间：
1991-05
期刊：
The Journal of cell biology
影响因子：
0
作者：
Greenberg S;el Khoury J;di Virgilio F;Kaplan EM;Silverstein SC
通讯作者：
Silverstein SC

P2Z adenosine triphosphate receptor activity in cultured human monocyte-derived macrophages.

DOI：
10.1182/blood.v84.8.2452.bloodjournal8482452
发表时间：
1994-10
期刊：
Blood
影响因子：
20.3
作者：
Suzanne E. Hickman;J. E. Khoury;Steven Greenberg;I. Schieren;Samuel C. Silverstein
通讯作者：
Suzanne E. Hickman;J. E. Khoury;Steven Greenberg;I. Schieren;Samuel C. Silverstein

A fluorescence technique to distinguish attached from ingested erythrocytes and zymosan particles in phagocytosing macrophages.

一种荧光技术，用于区分吞噬巨噬细胞中附着的红细胞和酵母聚糖颗粒。