HISTAMINE INDUCED ACCUMULATION OF T CELLS IN THE LUNG

组胺诱导 T 细胞在肺部积聚

• 批准号: 2217090
• 负责人: DAVID M. CENTER
• 金额: $ 33.31万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-06-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2217090
• 关键词: CD4 molecule; T lymphocyte; biological signal transduction; chemical binding; chemoattractants; genetic manipulation; histamine; lung disorder; lymphokines; membrane activity; membrane proteins; molecular cloning; monoclonal antibody; mutant; nucleic acid sequence; protein kinase C; protein purification; surface antigens; tissue /cell culture; CD4 molecule; T lymphocyte; biological signal transduction; chemical binding; chemoattractants; genetic manipulation; histamine; lung disorder; lymphokines; membrane activity; membrane proteins; molecular cloning; monoclonal antibody; mutant; nucleic acid sequence; protein kinase C; protein purification; surface antigens; tissue /cell culture

The studies proposed in this competitive renewal are designed to continue to define the structural and biologic characteristics of a lymphokine, Lymphocyte Chemoattractant Factor (LCF), described in our laboratory in 1982. Our original project was funded to design novel schemes for purification of LCF. These schemes were to be based upon our observations that this lymphokine was selectively secreted by histamine type 2 receptor bearing T cells in serum free media. The ultimate goals were to utilize purified material to study the way non-sensitized T cells are attracted into inflammatory foci and to achieve sufficient quantities of pure material for binding studies. In the course of the current grant period, several important discoveries about LCF have heightened its potential importance. Briefly summarized, LCF binds specifically to human CD4, inducing rises in intracellular levels of Ca and inositol trisphosphate. Subsequently, motile responses and upregulation of MHC Class II surface antigens and IL2 receptors occur. Despite these activation events following exposure to LCF, no IL2 secretion occurs and no DNA synthesis takes place. Thus, LCF is, by definition, a CD4+ T cell competence-type growth factor, and it is a natural ligand for CD4. CD4 may therefore participate in multiple ways in the T cell inflammatory process, now including amplification of the accumulation of CD4+ T cells and monocytes via both chemoattractant and growth factor activity. In order to understand the structure-function binding relationship between LCF and CD4, and understand this ligand's CD4-related membrane signal transduction complex, we propose, in this application, to complete cDNA and genomic cloning of LCF, characterize its specific binding site on CD4, and identify other membrane proteins associated with CD4 signalling, (including a Pertussis Toxin G protein, tyrosine kinase activity and other T cell membrane associated proteins). We believe these studies are a logical extension of the original grant, while potentially providing new insights into the function of a major differentiation antigen, CD4.

该竞争更新中提出的研究旨在继续 为了定义淋巴因子的结构和生物学特征， 淋巴细胞趋化因子（LCF），在我们的实验室中描述 1982年。我们的原始项目资助用于设计新颖的计划 LCF的纯化。这些方案是基于我们的观察 这种淋巴因子被组胺2型受体选择性分泌 在无血清培养基中轴承T细胞。最终目标是利用 纯化的材料研究非敏化T细胞的吸引方式 进入炎症焦点并获得足够数量的纯净 结合研究的材料。在当前赠款期间， 关于LCF的几个重要发现提高了其潜力 重要性。简而言之，LCF专门与人类CD4结合， 诱导细胞内Ca和肌醇三磷酸盐的升高。 随后，MHC II类表面的运动反应和上调 发生抗原和IL2受体。尽管有这些激活事件 暴露于LCF，没有发生IL2分泌，也不会发生DNA合成。 因此，根据定义，LCF是CD4+ T细胞能力类型生长因子， 它是CD4的天然配体。因此，CD4可能参与 T细胞炎症过程中的多种方式，包括 通过两者都放大CD4+ T细胞和单核细胞的积累 化学吸引剂和生长因子活性。为了了解 LCF和CD4之间的结构功能结合关系，并了解 该配体的CD4相关膜信号转导复合物，我们提出， 在此应用中，要完成LCF的cDNA和基因组克隆 表征其在CD4上的特定结合位点，并识别其他膜 与CD4信号相关的蛋白质（包括百日咳毒素G 蛋白质，酪氨酸激酶活性和其他T细胞膜相关 蛋白质）。我们认为这些研究是原始的逻辑扩展 授予，同时有可能提供有关一个功能的新见解 主要分化抗原，CD4。