Enhancement of Dendritic Cells After Burn Injury

烧伤后树突状细胞的增强

• 批准号: 7089920
• 负责人: Tracy E TOLIVER-KINSKY
• 金额: $ 23.59万
• 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/7089920
• 关键词: RNase protection assay; antibody formation; antigen presentation; bactericidal immunity; burns; cell population study; cell proliferation; cellular immunity; cytokine; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; immune response; immunoglobulin isotypes; laboratory mouse; leukocyte activation /transformation; opportunistic infections; pathologic process; phosphorylation; protein tyrosine kinase; statistics /biometry; wound healing; wound infection

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）：严重烧伤的患者有院内感染的风险，可延长住院时间，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作用，还因为大多数免疫细胞（包括抗原呈递细胞和效应淋巴细胞）的反应发生了改变。树突状细胞是抗原呈递细胞，激活先天和获得性免疫反应。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微生物功能。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核心作用，增强烧伤患者的树突状细胞可能会增加其对感染的抵抗力。fms样酪氨酸激酶-3配体（Flt3L）是一种造血细胞因子，可刺激骨髓源性祖细胞产生树突状细胞。用外源性Flt3L治疗可显著提高人类和啮齿动物的树突状细胞数量，增加正常小鼠对通常致命感染的抵抗力，并防止细菌攻击后由皮肤引起的早期IL-12和ifn - γ产生损伤。这一建议解决了一个假设，即通过Flt3L治疗烧伤小鼠的树突状细胞扩增可以增加其对感染的抵抗力。这将通过以下目的进行测试：1)检测Flt3L治疗烧伤小鼠获得性免疫的激活情况。树突状细胞促进T细胞分化、抗原特异性抗体产生和免疫球蛋白同型谱将被检查；2)测定Flt3L增加小鼠对进行性烧伤感染的抵抗能力。将检查烧伤创面感染后的细菌清除率、存活率和细胞因子反应；3)探讨树突状细胞对flt3l处理烧伤小鼠免疫增强的作用。我们将过继性地将树突状细胞转移到烧伤小鼠中，并消耗fltsl治疗的烧伤小鼠的树突状细胞，并评估目标1和目标2中的免疫功能。这些研究将确定严重烧伤后树突状细胞的射频增强可以增加对烧伤感染的抵抗力，并将确定树突状细胞对特定免疫功能的贡献。