ANTIGEN MODULATION OF T CELL CYTOKINE PROFILE

T 细胞细胞因子谱的抗原调节

• 批准号: 2856051
• 负责人: Brian D Evavold
• 金额: $ 10.82万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856051
• 关键词: T cell receptor; cell differentiation; cytokine; genetically modified animals; helper T lymphocyte; herpes simplex virus 1; interferon gamma; interleukin 10; interleukin 2; interleukin 4; laboratory mouse; leukocyte activation /transformation; polymerase chain reaction; protein biosynthesis; tissue /cell culture; tumor necrosis factor alpha

The overall theme of this project is to identify the extent to which analogs of immunogenic peptide can influence and alter the phenotype of T helper cells. This is important not just for manipulation of the immune response, but also to deepen our understanding of the mechanisms responsible for the polarization of response towards a Th1 or Th2 phenotype. The fundamental hypothesis of this study is that the phenotype of T cells (cytokine response) will vary as a function of the stimulatory peptide ligand. In the following three aims, the goals are to identify mechanisms by which peptide shifts precursor Th0 cells in vitro (aim I), extend this information to model antigens in vivo (aim II), and apply our findings to a viral pathogen (aim III). AIM I- Analysis of the effect of partial agonists/ antagonists peptide variants on the differentiation of Th0 cells in vitro. The hypothesis underlying this aim is that analogs of immunogenic peptide can selectively activate Th0 cell functional responses and promote the differentiation into a defined Th1 or Th2 phenotype. The experimental approach will focus on three possible mechanisms by which peptide could drive the differentiation of Th0 clones which are: 1) the selective down-modulation of the IL-2 response (an anergic state), 2) the specific activation of the Th2 cytokine profile, and 3) alter the effective dose of antigen (antagonism). AIM II- Analysis of the effect of partial agonists/ antagonists peptide variants on the differentiation of Th0 cells in vivo. This aim will test the hypothesis that analogs of immunogenic peptide can selectively influence the Th response in vivo. The experimental approach will be to inject altered peptide ligands of the well-defined model antigens from aim I into inbred and TCR transgenic mice and determine the Th phenotype and precursor T cell frequency. AIM III- Analysis of a Herpes simplex-1 viral epitope and manipulation of the phenotype of the T cell response. This aim will continue to test the hypothesis that antigen can control Th response in vivo with the additional factor of influencing the response to the herpes simplex-1 pathogen. The goal of these experiments will be to apply the protocol(s) identified in aims I and II to the multi-antigenic HSV-1 pathogen. These aims are expected to accomplish our broad objectives through the use of variants of antigenic peptides to manipulate and control the Th cell response.

本项目的总体主题是确定 免疫原性肽的类似物可以影响和改变表型 辅助性T细胞这不仅对操纵 免疫反应，也加深了我们对机制的理解 负责对Th 1或Th 2的反应极化 表型这项研究的基本假设是， T细胞的表型（细胞因子应答）将作为细胞因子的函数而变化。 刺激肽配体。在以下三个目标中，目标是 为了确定肽转移前体Th 0细胞的机制， 体外（目的I），将该信息扩展到体内模型抗原（目的 II），并将我们的研究结果应用于病毒病原体（目的III）。 目的I-分析部分激动剂/拮抗剂肽的作用 变体对Th 0细胞体外分化的影响。的假设 该目的的基础是免疫原性肽的类似物可以 选择性激活Th 0细胞功能性反应，并促进 分化为确定的Th 1或Th 2表型。实验 这种方法将集中在三种可能的机制，肽可以 驱动Th 0克隆的分化，这些克隆是：1）选择性的 下调IL-2反应（无反应性状态），2） Th 2细胞因子谱的特异性激活，和3）改变 有效剂量的抗原（拮抗作用）。 目的II-分析部分激动剂/拮抗剂肽的作用 变体对体内Th 0细胞分化的影响。这一目标将 测试免疫原性肽的类似物可以选择性地 影响体内Th反应。实验方法将是 为了注射定义明确的模型抗原的改变的肽配体 从目的I导入近交系和TCR转基因小鼠，并测定Th 表型和前体T细胞频率。 目的III-单纯疱疹病毒表位的分析和操作 T细胞反应的表型。这一目标将继续考验 假设抗原可以控制Th反应在体内与 影响对单纯疱疹-1反应的额外因素 病原体这些实验的目标是应用 多抗原HSV-1的目标I和II中确定的方案 病原体 这些目标预计将通过以下途径实现我们的广泛目标： 抗原肽变体在操纵和控制Th细胞中的用途 细胞反应。