Enhancement of Dendritic Cells After Burn Injury

描述（由申请人提供）：严重烧伤的患者有发生院内感染的风险，这会延长住院时间并增加发病率和死亡率。这不仅是由于皮肤失去了保护屏障，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。树突状细胞是激活先天性和获得性免疫反应的抗原呈递细胞。树突状细胞产生激活中性粒细胞、巨噬细胞和自然杀伤细胞杀菌功能的细胞因子。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，烧伤患者树突状细胞的增强可能会提高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，可刺激骨髓来源的祖细胞产生树突状细胞。用外源性 Flt3L 治疗可显着增加人类和啮齿动物的树突状细胞数量，增强正常小鼠对通常致命的感染的抵抗力，并防止细菌攻击后烧伤引起的早期 IL-12 和 IFN-γ 产生损伤。该提案提出了这样的假设：通过 Flt3L 治疗，烧伤小鼠的树突状细胞扩张可以增强其对感染的抵抗力。这将通过以下目标进行测试：1) 检查用 Flt3L 治疗的烧伤小鼠的获得性免疫的激活。将检查树突状细胞对 T 细胞分化的促进、抗原特异性抗体的产生和免疫球蛋白同种型谱； 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) 检查树突状细胞对 Flt3L 治疗烧伤小鼠免疫力增强的贡献。我们将过继地将树突状细胞转移到烧伤小鼠体内，并消耗 FltSL 治疗的烧伤小鼠的树突状细胞，并按照目标 1 和 2 评估免疫功能。这些研究将确定严重烧伤后树突状细胞的射频增强是否可以增加对烧伤伤口感染的抵抗力，并将确定树突状细胞对特定免疫功能的贡献。

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.