REGULATION OF CD4+ T CELL DIFFERENTITION BY CD8+ T CELLS

申请者致力于学术医学的职业生涯。他 设想了一种将基础科学应用于 临床医学。拟议的研究计划旨在增强 并加强申请人的免疫学知识和技能 基础科学方法论将是发展的关键 作为内科科学家的职业。 具体的研究建议源于申请人长期以来的 对T淋巴细胞的兴趣及其在过敏和感染中的作用 疾病。申请者将他的研究重点放在免疫反应上 呼吸道合胞病毒(RSV)对人类的重要性 病原体及其与慢性呼吸道疾病的关系 作为哮喘。申请人已经建立了呼吸道合胞病毒的小鼠模型 感染。最近发表的一项有趣的发现是 对RSV附着性糖蛋白致敏的小鼠产生强烈的T细胞 高水平产生IL-4和IL-5的细胞反应 使这些动物容易患上肺嗜酸性粒细胞增多症。这个 这些小鼠的肺部病理与人类的病理相似。 接受福尔马林治疗后发生严重呼吸道合胞病毒肺炎4例 RSV灭活疫苗。这种小鼠模型提供了一个独特的机会 探讨CD_4~+T淋巴细胞分化的机制及临床意义 T淋巴细胞在这一重要病毒感染中的作用。 申请人最近的研究表明，CD8+T淋巴细胞可能在 在调节CD4+T细胞分化中起重要作用。 RSV-1致敏小鼠诱导CD8+T细胞应答的实验研究 黏附糖蛋白抑制IL-4和IL-5的产生 以及肺嗜酸性粒细胞增多症的发展。这件事的重点是 建议研究CD8+T细胞发挥作用的机制 它们对CD4+T细胞分化的调节作用。 采用体外和体内两种模型，观察不同药物对细胞因子激活的影响。 呼吸道合胞病毒特异性CD8+T细胞对CD4+T细胞分化的影响 我们将检查CD4+T细胞成熟的不同阶段。这部作品 将提供对CD4+T细胞分化过程的洞察 将对设计一种有效的疫苗具有重要意义 这种重要的病毒。

The applicant is committed to a career in academic medicine. He envisions a career in which basic science is applied to the problems in clinical medicine. The proposed research program is designed to enhance and strengthen the applicant's knowledge in immunology and his skill in basic science methodology which will be crucial to the development of a career as a physician scientist. The specific research proposal arises from the applicant's long-standing interest in T lymphocytes and their roles in allergic and infectious disease. The applicant has focused his research on the immune responses to Respiratory Syncytial Virus (RSV) because of its importance as human pathogen as well as its association with chronic airway diseases such as asthma. The applicant has established a murine model of RSV infection. An interesting finding which has been recently published is that mice sensitized to RSV-attachment glycoprotein develop a strong T cell response with high levels of IL-4 and IL-5 production which predisposes these animals to the development of lung eosinophilia. The lung pathology of these mice resembles the pathology observed in human cases that developed severe RSV pneumonia after receiving the formalin inactivated RSV vaccine. This murine model provides a unique opportunity to study the mechanisms of CD4+ T lymphocyte differentiation and the roles of T lymphocytes in this important viral infection. Recent studies by the applicant suggest that CD8+ T lymphocytes may play an important role in the regulation of CD4+ T cell differentiation. Induction of a strong CD8+ T cell response in mice sensitized to RSV- attachment glycoprotein suppresses the production of IL-4 and IL-5 as well as the development of lung eosinophilia. The focus of this proposal is to investigate the mechanisms by which CD8+ T cells exert their regulatory functions on the differentiation of CD4+ T cells. Using both in vitro and in vivo model, the impact of the activation of RSV-specific CD8+ T cells on the differentiation of CD4+ T cells at various stages of CD4+ T cell maturation will be examined. This work will provide insight into the process of CD4+ T cell differentiation and will have significance to the design of an effective vaccine against this important virus.