Regulatory T Cells Through the Indirect Pathway

通过间接途径调节 T 细胞

• 批准号: 7159382
• 负责人: A BENEDICT COSIMI
• 金额: $ 32.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7159382
• 关键词: Adoptive Transfer; Allogenic; Antigens; Atypical lymphocyte; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Class; Condition; DNA Microarray Chip; DNA Microarray format; Data; Development; Diagnostic; Graft Rejection; Heart Transplantation; Histocompatibility Antigens Class II; Knowledge; Lymphoid; MHC antigen; Modeling; Mus; Numbers; Organ; Pathway interactions; Peptides; Population; Property; Research Personnel; Specificity; System; T-Lymphocyte; Testing; Tissues; Transplantation; Work; base; enzyme linked immunospot assay; prevent; research study; response

Regulatory T cells contribute to the prolonged survival of allogeneic tissues under some conditions. Many investigators have characterized regulatory cells by their phenotypie markers (such as CD4+CD25+) and others have tried to determine the mechanisms by which they work. In studies of allogeneic cardiac transplantation in mice using costimulatory blockade, we found that prolonged survival could not be achieved in recipients that lacked MHC class II molecules. This suggested that regulatory T cells might be generated through the indirect pathway. We have now accumulated additional preliminary data, using an adoptive transfer system, indicating that donor-specific CD4+CD25+ regulatory cells are specific for indirect determinants. In addition, the data are consistent with a model in which: 1) Peptides of donor iVIt/C antigens are primarily responsible for generating the indirect determinants for this regulatory population, which functions by preventing activation of donor-reactive lymphocytes in secondary lymphoid organs. 2) An additional population of self-specific, CD4+ regulatory T cells is also be generated that can prevent the effector function of donor-reactive lymphocytes, but not their activation, if the self determinant is expressed in the donor graft. 3) CD8+ cells alter the regulatory response, perhaps by producing additional populations of regulatory T cells. The experiments proposed in this application will focus on the specificity of regulatory T cells in transplantation, which will enable us to separate distinct subpopulations of these cells. We will test our proposed model by pursuing three specific aims that examine the different regulatory T cell subpopulations. The experiments in the fourth specific aim will use the information about their specificity to compare mechanistic properties of the regulatory T cell subpopulations and to develop diagnostic assays to detect their presence.

调节性T细胞有助于某些同种异体组织的长期生存率 状况。许多研究人员通过其表型标记来表征调节细胞（例如 CD4+CD25+）和其他人试图确定它们起作用的机制。 在使用共刺激封锁的小鼠中同种异体心脏移植的研究中，我们发现 在缺乏MHC II类分子的受体中，无法实现延长的生存率。这 建议可以通过间接途径产生调节性T细胞。我们现在有 使用收养转移系统累积了其他初步数据，表明 供体特异性的CD4+ CD25+调节细胞是间接决定因素的特异性。另外， 数据与以下模型一致：1）供体IVIT/C抗原的肽主要是 负责为该监管人群生成间接决定因素，该决定因素通过 防止次要淋巴器官中供体反应性淋巴细胞的激活。 2）附加 还会产生自我特异性的CD4+调节T细胞的种群，以防止效应子 供体反应性淋巴细胞的功能，而不是其激活的功能，如果在 捐赠者移植物。 3）CD8+细胞改变调节响应，也许通过产生额外 调节T细胞的种群。 本应用中提出的实验将集中于调节T细胞中的特异性 移植，这将使我们能够分离这些细胞的不同亚群。我们将测试我们的 提出的模型通过追求检查不同的调节T细胞的三个特定目标 亚群。第四个特定目标中的实验将使用有关其的信息 比较调节性T细胞亚群的机理特性的特异性和 开发诊断测定以检测其存在。