T CELL SUBSETS IN MURINE MYCOPLASMA RESPIRATORY DISEASE

描述（改编自申请人的摘要）：广泛，长期 本项目的目的是确定免疫和炎症 影响支原体进展和耐药性的反应 呼吸系统疾病，并将此信息应用于开发有效的 支原体疾病的免疫疗法。具体目标是：（1） 确定CD 4+和CD 8 + T细胞在小鼠支原体呼吸道感染中的作用 2）检查IFN-γ和IL-4在支原体疾病中的作用;和 3)确定T辅助细胞亚群反应在产生保护性免疫应答中的作用。 抗支原体感染免疫力。支原体呼吸道疾病有一个 对美国的健康产生了巨大的影响。有8到1500万人 每年在美国的案件。很明显，免疫反应 对支原体呼吸道疾病的进展有重大影响。 免疫在抵抗疾病和从疾病中恢复方面确实起作用，但主要是 支原体呼吸道疾病的一个重要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发挥作用。以前的工作表明，T 细胞在决定宿主的反应是否有益于 或有害的。然而，不同T细胞亚群的作用尚不清楚。 这些信息将为了解疾病过程提供重要的见解， 建立治疗和预防支原体病新方法 人类实验设计如下：1）小鼠将用 单克隆抗体以消耗CD 4+和/或CD 8 + T细胞和严重程度 支原体引起的支原体呼吸道疾病的小鼠模型 肺，将被确定。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， 2）IFN-γ和IL-4敲除小鼠将感染 将确定支原体和疾病的严重程度以及支原体的数量。 此外，正常小鼠将用特异于这些抗体的单克隆抗体治疗。 细胞因子在感染后的不同时间，以确定疾病的阶段 这些细胞因子发挥作用;和3）用IFN-γ或IL-4处理的小鼠 特异性单克隆抗体，将用支原体抗原免疫，和 将测定它们随后对支原体病的抗性。还有， 将用与Th 1（IL-12）或Th 2（IL-12）混合的支原体抗原免疫小鼠 （IL-4）促进细胞因子和保护免受支原体感染将是 评估。这些结果将有助于进一步研究发病机制， 预防鼠支原体呼吸道疾病，并为 支原体引起的人类呼吸道疾病的研究重要的是这些 研究将有助于制定一种创新的方法， 支原体疾病依赖于我们对免疫学的理解， 疾病的发病机制和选择性激活 T辅助细胞亚群，以最大限度地保护，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.