Dendritic cells & immunity in mycoplasma pneumonia

树突状细胞

• 批准号: 7007280
• 负责人: Jerry W Simecka
• 金额: $ 27.73万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7007280
• 关键词: T cell receptor; T lymphocyte; cell differentiation; cellular immunity; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; laboratory mouse; leukocyte activation /transformation; macrophage; mycoplasmal pneumonia; polymerase chain reaction; respiratory disease /disorder therapy

DESCRIPTION (provided by applicant): The broad, long-term objectives of this project are to develop approaches to prevent and treat respiratory diseases. We found that different T cells populations modulate inflammatory responses of murine mycoplasma pneumonia, and the factors that determine the type of T cell responses need to be understood. The role of dendritic cells (DCs) and other antigen presenting cells, e.g. macrophages, in Mycoplasma disease is unknown, but because T cell responses in mycoplasma disease play such a critical role, DCs and macrophages likely impact on disease pathogenesis and influence the generation of protective immunity. We hypothesize that manipulating DC can predictably change the types and intensity of immune reactions in the lung against mycoplasma infection, and this will impact on the severity and resistance to disease. In addition, pulmonary macrophages may also impact on mycoplasma immunity, possibly through support of Th1-type responses. The impact of pulmonary DCs and macrophages activity needs to be compared. In this proposal, we will address the following questions: 1) Do changes in pulmonary DCs and macrophages from naive or mycoplasma-infected mice influence the ability to activate and modulate T cell differentiation and activation? 2) Can mycoplasma-antigen pulsed DCs or macrophages generate protective or immunopathologic responses against mycoplasma? 3) Can altering DC function with regulatory cytokines influence pulmonary immune responses and mycoplasma respiratory disease? 4) Do the DCbeta-chemokines, ABCD-1 and ABCD-2 (TARC), play a role in pulmonary immunity against mycoplasma? The experimental design is as follows: 1) DCs and macrophages from the respiratory tracts of mycoplasma-infected mice will be evaluated for their ability activate in vitro and in vivo T cell responses against an unrelated antigen (OVA). 2) DCs and macrophages will be pulsed with mycoplasma antigen and their ability to generate resistance or immunopathology after intratracheal inoculation and subsequent challenge with mycoplasma will be determined. 3) DC will be treated in vitro with regulatory cytokines, IFNgamma, IL-12, IL-4 TGF-beta or IL-10, and pulsed with mycoplasma antigen, and their ability to generate resistance or immunopathology against mycoplasma will be determined by their intratracheal inoculation; and 4) T cells from lungs of Mycoplasma infected mice will be examined for expression of receptors for ABCD-1 and ABCD-2 and their ability to respond to these chemokines. Mice will be treated with neutralizing monoclonal antibodies to determine the role of ABCD-1 and ABCD-2 in protective immunity and immunopathologic responses against mycoplasma.

描述（由申请人提供）：该项目的广泛，长期目标是开发预防和治疗呼吸系统疾病的方法。我们发现，不同的T细胞群调节小鼠支原体肺炎的炎症反应，和T细胞反应的类型的决定因素需要了解。树突状细胞（DC）和其他抗原呈递细胞（例如巨噬细胞）在支原体疾病中的作用尚不清楚，但由于T细胞应答在支原体疾病中起如此关键的作用，DC和巨噬细胞可能影响疾病发病机制并影响保护性免疫的产生。我们假设，操纵DC可以可预测地改变肺中针对支原体感染的免疫反应的类型和强度，这将影响疾病的严重程度和抵抗力。此外，肺巨噬细胞也可能通过支持Th 1型应答影响支原体免疫。需要比较肺DC和巨噬细胞活性的影响。在这个提议中，我们将解决以下问题：1）从幼稚或支原体感染的小鼠肺DC和巨噬细胞的变化是否影响激活和调节T细胞分化和激活的能力？2)支原体抗原致敏的树突状细胞或巨噬细胞能否产生抗支原体的保护性或免疫病理反应？3)调节性细胞因子改变DC功能能否影响肺免疫应答和支原体呼吸道疾病？4)DC β趋化因子ABCD-1和ABCD-2（TARC）在肺抗支原体免疫中是否起作用？实验设计如下：1）将评估来自支原体感染小鼠的呼吸道的DC和巨噬细胞在体外和体内激活针对不相关抗原（OVA）的T细胞应答的能力。2)将用支原体抗原脉冲DC和巨噬细胞，并测定其在气管内接种和随后用支原体激发后产生抗性或免疫病理学的能力。3)DC将在体外用调节性细胞因子IFN γ、IL-12、IL-4、TGF-β或IL-10处理，并用支原体抗原脉冲，并且它们产生针对支原体的抗性或免疫病理学的能力将通过它们的体内接种来确定;和4）检测来自支原体感染小鼠肺的T细胞的ABCD-1和ABCD-2受体的表达。2和它们对这些趋化因子的反应能力。将用中和单克隆抗体处理小鼠，以确定ABCD-1和ABCD-2在针对支原体的保护性免疫和免疫病理学应答中的作用。