Enhancement of Dendritic Cells After Burn Injury

烧伤后树突状细胞的增强

• 批准号: 7253380
• 负责人: Tracy E TOLIVER-KINSKY
• 金额: $ 22.91万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253380
• 关键词: Address; Adoptive Transfer; Affect; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocytes; Bacteria; Bone Marrow; Burn injury; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cellular Immunity; Cessation of life; Clonal Expansion; Coculture Techniques; Dendritic Cells; Development; Differentiation Antigens; Growth; Helper-Inducer T-Lymphocyte; Hospitalization; Human; Immune; Immune response; Immunity; Immunoglobulin Isotypes; Immunoglobulins; Impairment; Infection; Injury; Interferon Type II; Interleukin-12; Interleukin-15; Lactated Ringer' s Solution; Lead; Ligands; Lymphocyte; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Natural Killer Cells; Nosocomial Infections; Numbers; Opportunistic Infections; Organ; Patients; Phenotype; Play; Population; Predisposition; Production; Property; Pseudomonas aeruginosa; Regulation; Research; Research Personnel; Resistance; Resistance to infection; Risk; Rodent; Role; Sepsis; Skin; Stem cells; T-Cell Proliferation; T-Lymphocyte; T-lymphocyte differentiation antigen; Testing; Time; Vascular Endothelial Growth Factor Receptor-1; Wound Healing; Wound Infection; Wounds and Injuries; acquired immunity; cell mediated immune response; cell type; clinically relevant; cytokine; day; immune function; improved; in vivo; insight; killer T cell; killings; macrophage; microbicide; microorganism; mortality; neutrophil; pathogen; prevent; programs; research study; response; treatment effect; wound

DESCRIPTION (provided by applicant): Patients with severe bums are at risk for the development of nosocomial infections that can prolong hospitalization and increase morbidity and mortality. This is due not only to loss of the skin as a protective barrier, but also to altered responses of most immune cells, including antigen-presenting cells and effector lymphocytes. Dendritic cells are antigen presenting cells that activate both innate and acquired immune responses. Dendritic cells produce cytokines that activate neutrophil, macrophage, and natural killer cell microbicidal functions. Dendritic cells interact with T cells to promote cell differentiation and activation, and promote the humoral response. Given the central role of dendritic cells in promoting immune responses, enhancement of dendritic cells in bum patients may increase their resistance to infections. Fms-like tyrosine kinase-3 ligand (Flt3L) is a hemopoietic cytokine that stimulates the production of dendritic cells from bone marrow-derived progenitor cells. Treatment with exogenous Flt3L dramatically enhances dendritic cell numbers in humans and rodents, increases the resistance of normal mice to infections that are typically lethal, and prevents bum-induced impairments in early IL-12 and IFN-gamma production after bacterial challenge. This proposal addresses the hypothesis that expansion of dendritic cells in burned mice by Flt3L treatments can increase their resistance to infections. This will be tested through the following aims: 1) To examine activation of acquired immunity in burned mice treated with Flt3L. Dendritic cell promotion of T cell differentiation, antigen-specific antibody production, and immunoglobulin isotype profiles will be examined; 2) To determine the ability of Flt3L to increase the resistance of mice to a progressive bum wound infection. Bacterial clearance, survival, and cytokine responses after burn wound infection will be examined; 3) To examine the contribution of dendritic cells to enhanced immunity in Flt3L-treated burned mice. We will both adoptively transfer dendritic cells into burned mice and deplete FltSL-treated burned mice of dendritic cells, and assess immune function as in aims 1 and 2. These studies will determine rf enhancement of dendritic cells after severe bums can increase resistance to bum wound infection, and will determine the contribution of dendritic cells to specific immune functions.

描述(由申请人提供)：严重烧伤的患者有发生医院感染的风险，这可能会延长住院时间，增加发病率和死亡率。这不仅是因为皮肤失去了作为保护屏障的皮肤，还因为大多数免疫细胞的反应发生了变化，包括抗原提呈细胞和效应性淋巴细胞。树突状细胞是一种抗原提呈细胞，能激活先天免疫反应和获得性免疫反应。树突状细胞产生细胞因子，激活中性粒细胞、巨噬细胞和自然杀伤细胞的杀菌功能。树突状细胞与T细胞相互作用，促进细胞分化和活化，促进体液反应。鉴于树突状细胞在促进免疫反应中的中心作用，烧伤患者树突状细胞的增强可能会增强他们对感染的抵抗力。FMS样酪氨酸激酶-3配体(Flt3L)是一种造血细胞因子，能刺激骨髓来源的祖细胞产生树突状细胞。外源性Flt3L的治疗显著增加了人类和啮齿动物中的树突状细胞数量，增加了正常小鼠对通常致命的感染的抵抗力，并防止了细菌攻击后烧伤导致的早期IL-12和干扰素-γ产生的损害。这项建议解决了这样的假设，即通过Flt3L治疗在烧伤小鼠中扩增树突状细胞可以提高它们对感染的抵抗力。这将通过以下目的进行测试：1)检查用Flt3L治疗的烧伤小鼠获得性免疫的激活情况。将检测树突状细胞对T细胞分化、抗原特异性抗体产生和免疫球蛋白同型图谱的促进作用；2)确定Flt3L增加小鼠对进行性烧伤伤口感染的抵抗力的能力。将检测烧伤创面感染后的细菌清除、存活和细胞因子反应；3)检测树突状细胞在Flt3L治疗的烧伤小鼠增强免疫中的作用。我们将过继地将树突状细胞转移到烧伤小鼠体内，并耗尽FltSL治疗的烧伤小鼠的树突状细胞，并评估免疫功能，如目标1和2。这些研究将确定严重烧伤后树突状细胞的RF增强可以增强对烧伤创面感染的抵抗力，并将确定树突状细胞对特定免疫功能的贡献。