T CELL SUBSETS IN MURINE MYCOPLASMA RESPIRATORY DISEASE

描述(改编自申请人的摘要)：宽泛的、长期的 本项目的目的是确定免疫学和炎症性 对支原体的进展和耐药性有影响的反应 呼吸道疾病，并将这些信息应用于开发有效的 支原体疾病的免疫疗法。具体目标为1) CD_4~+和CD_8~+T细胞在小鼠支原体呼吸道感染中的作用 2)检测干扰素-γ和白介素4在支原体疾病中的作用；以及 3)确定T辅助细胞亚群反应在保护性免疫生成中的作用 对支原体感染的免疫力。支原体呼吸道疾病有一种 对美国的健康有巨大的影响。有800万到1500万 美国每年都有这样的病例。很明显，免疫反应 对支原体呼吸道疾病的进展有重大影响。 免疫确实在抵抗疾病和从疾病中恢复方面发挥作用，但主要的 支原体呼吸道疾病的组成部分是免疫病理。有一个 迫切需要了解免疫和炎症机制 在支原体呼吸道疾病中起作用。先前的工作表明，T 细胞在决定宿主反应是否有益的过程中起着关键作用 或者是有害的。然而，不同T细胞亚群的作用尚不清楚。 这些信息将提供对疾病过程和 建立治疗和预防支原体疾病的新方法 人类。实验设计如下：1)给小鼠灌胃给药 CD_4~+和/或CD_8~+T细胞耗竭的单抗及其严重程度 支原体引起的小鼠支原体呼吸道疾病模型的建立 肺气肿，将会被确定。此外，特定的T细胞亚群和B细胞将 过继转移到免疫缺陷的SCID小鼠，以及疾病的严重程度 2)干扰素-γ和白介素4基因敲除小鼠将感染 支原体和疾病的严重性和支原体的数量将被确定。 此外，正常小鼠将接受针对这些疾病的单抗治疗。 感染后不同时间细胞因子变化对疾病分期的影响 这些细胞因子发挥作用；3)用干扰素-γ或IL-4治疗的小鼠 特定的单抗，将用支原体抗原免疫，以及 他们随后对支原体疾病的抵抗力将被确定。另外， 用支原体抗原与Th1、IL-12或Th2混合免疫小鼠 (IL-4)促进细胞因子和保护支原体感染 评估过了。这些结果将为进一步研究发病机制和 为预防小鼠支原体呼吸道疾病提供启示 支原体引起的人类呼吸道疾病的研究。重要的是，这些 研究将有助于开发一种创新的作战方法 支原体疾病依赖于我们对免疫学的了解 疾病的发病机制与选择性激活 T辅助细胞亚群，在最大限度保护的同时最大限度地减少疾病和 炎症反应。

DESCRIPTION (Adapted from the applicant's abstract): The broad, long-term objective of this project is to determine the immunologic and inflammatory responses that have an impact on the progression and resistance to mycoplasma respiratory disease, and apply this information to development of effective immunotherapies against mycoplasma diseases. The Specific Aims are to 1) Determine the role of CD4+ and CD8+ T cells in murine mycoplasma respiratory disease; 2) Examine the effects IFN-gamma and IL-4 in mycoplasma disease; and 3) Determine the role of T helper subset responses in generation of protective immunity against mycoplasma infection. Mycoplasma respiratory disease has a tremendous impact on health in the United States. There are 8 to 15 million cases in the United States annually. It is clear that immunologic responses have a major impact on the progression of mycoplasma respiratory disease. Immunity does play a role in resisting and recovery from disease, but a major component of mycoplasma respiratory diseases is immunopathologic. There is a critical need to understand the immunologic and inflammatory mechanisms that play a role in mycoplasma respiratory disease. Previous work suggests that T cells play a pivotal role in determining whether host responses are beneficial or detrimental. However, the role of the different T cell subsets is unclear. This information will provide important insights into the disease process and establish novel approaches for therapy and prevention of mycoplasma disease in humans. The experimental design is as follows: 1) Mice will be treated with monoclonal antibodies to deplete of CD4+ and/or CD8+ T cells and the severity of a murine model of mycoplasma respiratory disease, caused by Mycoplasma pulmonis, will be determined. Also, specific T cell subsets and B cells will be adoptively transferred into immunodeficient SCID mice, and disease severity will be determined; 2) IFN-gamma and IL-4 knockout mice will be infected with mycoplasma and disease severity and numbers of mycoplasma will be determined. Also, normal mice will be treated with monoclonal antibodies specific for those cytokines at different times after infection to determine the stage of disease that these cytokines play a role; and 3) Mice, treated with IFN-gamma or IL-4 specific monoclonal antibodies, will be immunized with mycoplasma antigens, and their subsequent resistance to mycoplasma disease will be determined. Also, mice will be immunized with mycoplasma antigen mixed with Th1 9IL-12) or Th2 (IL-4) promoting cytokines and protection from mycoplasma infection will be assessed. These results will allow further studies on pathogenesis and prevention of murine mycoplasma respiratory disease and provide insights for studies on human respiratory disease due to mycoplasma. Importantly, these studies will facilitate development of an innovative approach to combat mycoplasma diseases that relies on our understanding of the immunologic mechanisms of disease pathogenesis and the preferential activation of selected T helper cell subsets to maximize protection while minimizing disease and inflammatory reactions.