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：
7421090
负责人：
SAMUEL CHARLES SILVERSTEIN
金额：
$ 37.88万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-07-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7421090
关键词：
Address Adhesions Affect Albumins Alcohols Amoxicillin Animal Model Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antibodies Antigen Receptors Antigens Apoptotic Area Attention Azacitidine Back Bacteria Bacterial Infections Bathing Beds Behavior Beta-glucuronidase Binding Biocompatible Materials Biological Assay Biopsy Blocking Antibodies Blood Blood Circulation Blood Vessels Blood flow Bone Marrow Brefeldin A Buffers C57BL/6 Mouse C5a anaphylatoxin receptor CCL2 gene CD8B1 gene CSF1 gene Caliber Capillary Endothelial Cell Cardiac Cartilage Catheters Cell Count Cell Line Cell membrane Cell physiology Cell surface Cells Centrifugation Chemotactic Factors Chlorates Class Coagulation Process Cobra Venoms Collaborations Collagen Complement Complement 3d Complement 5a Condition Conditioned Culture Media Count Cultured Cells Cyclic AMP-Dependent Protein Kinases Cycloheximide Cytochalasin D Cytolysis Cytoplasm Cytoplasmic Granules Cytoplasmic Organelle DNA Methylation Daily Data Defect Deposition Depth Dermal Dermis Development Digestion Doctor of Philosophy Dorsal Dose E-Selectin Ear Ear Cartilages Effector Cell Electron Microscopy Emigrations Endopeptidases Endothelial Cells Endothelium Enterotoxins Environment Enzyme-Linked Immunosorbent Assay Enzymes Equation Escherichia coli Evans blue stain Event Exhibits Fc Receptor Fibrin Fibrinogen Figs - dietary Fluorescence Foreign Bodies Formalin Fostering Frozen Sections Gel Gene Expression Generations Glycosaminoglycans Goals Golgi Apparatus Gram-Negative Bacteria Granulocyte-Macrophage Colony-Stimulating Factor Growth Growth Factor Haemophilus influenzae Hand Harvest Heart Heating Histones Host Defense Human ITGB2 gene Ice IgE Immigration Immune Immune response Immunity Immunization Immunoglobulin G Immunoglobulins Implant In Vitro Incubated Infection Infectious Diseases Research Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Integrins Interferons Interleukin-1 Interleukin-1 Receptors Interleukin-2 Intravenous infusion procedures Invaded Ketamine Kinetics Knock-out Knockout Mice Knowledge Label Laboratories Lead Learning Left Length Lesion Letters Leukocytes Leukotriene B4 Ligands Light Lipids Lipopolysaccharides Liposomes Literature Longevity Lung Lymphatic Lymphocyte Lysosomes MAPK14 gene MEKs Macrophage Colony-Stimulating Factor Measures Mediating Melanoma Cell Membrane Membrane Glycoproteins Methods Microbial Biofilms Microspheres Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Monitor Monoclonal Antibodies Monoclonal Antibody HuM291 Mononuclear Leukocytes Montana Morphology Mouse Strains Muromonab-CD3 Mus Myelogenous Myeloid Cells Natural Killer Cells Needles Nodule Normal Horse Serum Numbers Numerical value Organelles Organism Oryctolagus cuniculus Ovalbumin Ovum Oxidases PD-98059 Palpable Pathway interactions Peptide Hydrolases Peptides Percoll Perfusion Peroxidase Peroxidases Phagocytes Phagocytosis Phagosomes Phase Phenotype Phosphorylation Plasma Plasma Proteins Plastics Play Positioning Attribute Postdoctoral Fellow Predisposition Process Production Property Prosthesis Protein Biosynthesis Protein Phosphatase Inhibitor Proteins Proteoglycan Pseudomonas aeruginosa Punch Biopsy Puncture procedure Purpose Rain Rate Reader Reagent Recruitment Activity Regression Analysis Reporting Research Personnel Residual state Resistance Resolution Role SB 203580 Sampling Sepsis Serum Signal Pathway Signal Transduction Signaling Protein Site Skin Skin Temperature Sonication Source Speed Spleen Staining method Stains Staphylococcus aureus Sterility Sterilization for infection control Streptococcus pneumoniae Stromal Cells Structure Students Study models Sucrose Surface Surgical incisions Suspension substance Suspensions Swab Syringes System T-Lymphocyte TNF gene Teflon Temperature Tenascin Testing Thick Thinking Thrombin Time Tissue Extracts Tissue Stains Tissues Transgenes Transgenic Mice Trichostatin A Trypsin Tumor Antigens Tumor-Derived Uncertainty Universities Upper arm Vaccines Venous Virulence Factors Week Western Blotting Wild Type Mouse Work Wound Healing Xylazine absorption bactericide base blood flow measurement cancer cell carboxyfluorescein cell killing cell type chemokine collagenase complement C2a complement C5b concept culture plates cytokine cytotoxic day demethylation design desire eosinophil fluorophore human MAPK14 protein hydroxy-aluminum polymer immunogenic in vitro Assay in vitro Model in vivo inhibitor/antagonist insight interest interstitial killings kinase inhibitor lymph flow lymph nodes macrophage mast cell melanoma microbial migration mitogen-activated protein kinase p38 monocyte monolayer neoplastic cell neutralizing antibody neutrophil novel novel strategies oral infection pathogen peripheral blood pressure prevent protective effect quorum sensing receptor research study residence response size success sulfation surface coating symposium tissue culture tissue processing tumor tumorigenesis two-dimensional uptake

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 I 型胶原蛋白凝胶来比较组织样环境与搅拌悬浮液中的中性粒细胞 (PMN) 杀菌活性，并发现需要临界 PMN 浓度 (CNC) 来阻断纤维蛋白和胶原蛋白凝胶以及搅拌悬浮液中细菌的生长。执行特定免疫效应功能需要临界白细胞浓度的概念既新颖又重要。它统一了有关宿主防御细菌感染的大量文献，并提供了一个概念框架，用于定量评估必须递送到组织以执行特定功能的任何类别或类型的免疫细胞的浓度。我们推导出了一个方程，使我们能够计算迄今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（大约 4 x 105 PMN/ml）与已知的使中性粒细胞减少症人类易患败血症的 CNC 几乎相同，而纤维蛋白凝胶中的 CNC 则高出 2.5 - 10 倍（例如，1-4 x 106PMN/毫升）。使用这些凝胶，我们扩展了之前的观察结果，即特定基质蛋白（例如，纤维蛋白）和化学引诱剂（例如，fMLP）通过显示在纤维蛋白存在下，fMLP 阻断 PMN 杀菌活性来阻断 PMN 迁移。此外，我们发现，α2-整合素遗传缺陷的中性粒细胞吞噬和杀死表皮葡萄球菌的效率与纤维蛋白凝胶中的野生型中性粒细胞一样。我们还发现，与传统观点相反，PMN 有能力侵入并杀死成熟（5 天）生物膜中 98% 以上的表皮葡萄球菌。我们寻求持续的支持来扩展这些研究，并确定调节 PMN 和单核细胞从血液迁移到组织的机制，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细菌和生物膜细菌以及细胞毒性淋巴细胞杀死癌细胞。该应用程序具有三个具体目标。目标#1。体外测定纤维蛋白和 I 型胶原蛋白凝胶中单核细胞杀灭表皮葡萄球菌和大肠杆菌的临界浓度，以及体内杀灭表皮葡萄球菌和大肠杆菌的 PMN 和单核细胞的临界浓度，并鉴定发出中性粒细胞和单核细胞停止进入细菌感染真皮部位的信号的机制。目标#2。确定阻碍中性粒细胞和单核细胞杀灭生物材料相关表皮葡萄球菌生物膜的免疫机制。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在肿瘤床内达到临界浓度才能实现肿瘤质量的减少吗？