ANTIGEN MODULATION OF T CELL CYTOKINE PROFILE

T 细胞细胞因子谱的抗原调节

• 批准号: 2633576
• 负责人: Brian D Evavold
• 金额: $ 10.71万
• 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/2633576
• 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.

该项目的总体主题是确定以下方面的程度 免疫原肽类似物可以影响和改变表型。 T辅助细胞的数量。这一点不仅对于操纵 免疫反应，也加深了我们对机制的理解 对Th1或Th2反应的两极分化负责 表型。这项研究的基本假设是 T细胞的表型(细胞因子反应)会随着 刺激性多肽配体。在以下三个目标中，目标是 识别多肽转移Th0前体细胞的机制 体外(目标I)，将这一信息扩展到体内模型抗原(目标 Ii)，并将我们的发现应用于病毒病原体(AIM III)。 目的I-分析部分激动剂/拮抗剂多肽的作用 Th0细胞体外分化的突变体。假说 这一目标的基础是免疫原肽的类似物可以 选择性激活Th0细胞功能反应，促进 分化为明确的Th1或Th2表型。实验性的 方法将重点放在三种可能的机制上，通过这些机制 推动Th0克隆的分化：1)选择性克隆 下调IL-2反应(一种无能状态)，2) Th2细胞因子的特异性激活，以及3)改变 抗原有效剂量(拮抗)。 目的II-分析部分激动剂/拮抗剂多肽的作用 体内Th0细胞分化的变异。这一目标将 检验免疫原肽类似物可以选择性地 影响体内Th反应。实验方法将是 注射明确定义的模型抗原的改变的多肽配体 从AIM 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1型表位的分析及操作 T细胞反应的表型。这一目标将继续受到考验 抗原可在体内控制Th反应的假说 影响单纯疱疹病毒1型应答的其他因素 病原体。这些实验的目标将是将 多抗原型单纯疱疹病毒1型AIMS I和II中确定的方案(S) 病原体。 预计这些目标将通过以下途径实现我们的广泛目标 利用抗原肽的变异体操控Th 细胞反应。