Enhancement of Dendritic Cells After Burn Injury

描述（由申请方提供）：重度烧伤患者存在发生医院感染的风险，这可能延长住院时间并增加发病率和死亡率。这不仅是由于皮肤作为保护屏障的丧失，而且是由于大多数免疫细胞（包括抗原呈递细胞和效应淋巴细胞）的反应改变。树突状细胞是激活先天性和获得性免疫应答的抗原呈递细胞。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微生物功能的细胞因子。树突状细胞与T细胞相互作用，促进细胞分化和活化，并促进体液反应。鉴于树突状细胞在促进免疫反应中的核心作用，烧伤患者中树突状细胞的增强可能会增加其对感染的抵抗力。Fms样酪氨酸激酶-3配体（Flt 3L）是一种造血细胞因子，其刺激骨髓来源的祖细胞产生树突状细胞。用外源Flt 3L治疗显著提高了人类和啮齿动物中树突状细胞的数量，增加了正常小鼠对通常致命的感染的抵抗力，并防止细菌攻击后早期IL-12和IFN-γ产生中的烧伤诱导的损伤。该提案解决了Flt 3L治疗烧伤小鼠中树突状细胞扩增可以增加其对感染的抵抗力的假设。这将通过以下目的进行测试：1）检查用Flt 3L处理的烧伤小鼠中获得性免疫的激活。将检查树突状细胞促进T细胞分化、抗原特异性抗体产生和免疫球蛋白同种型谱; 2）确定Flt 3L增加小鼠对进行性烧伤伤口感染的抗性的能力。将检查烧伤伤口感染后的细菌清除、存活和细胞因子应答; 3）检查树突状细胞对Flt 3L处理的烧伤小鼠中增强的免疫力的贡献。我们将过继性地将树突状细胞转移到烧伤小鼠中并耗尽FltSL处理的烧伤小鼠的树突状细胞，并如目标1和2中那样评估免疫功能。这些研究将确定严重烧伤后射频增强树突状细胞可以增加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。

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.