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 细胞有助于同种异体组织在某些条件下延长存活时间 状况。许多研究人员通过表型标记（例如 CD4+CD25+）和其他人试图确定它们的工作机制。 在使用共刺激阻断的小鼠同种异体心脏移植研究中，我们发现 缺乏 MHC II 类分子的受体无法实现延长生存期。这 表明调节性T细胞可能是通过间接途径产生的。我们现在有 使用收养转移系统积累了额外的初步数据，表明 供体特异性 CD4+CD25+ 调节细胞对间接决定因素具有特异性。此外， 数据与模型一致，其中：1) 供体 iVIt/C 抗原的肽主要是 负责为该调节群体产生间接决定因素，其功能是 防止次级淋巴器官中供体反应性淋巴细胞的激活。 2) 额外的 还产生了自我特异性的 CD4+ 调节性 T 细胞群，可以阻止效应子 供体反应性淋巴细胞的功能，但不是它们的激活，如果自决因子表达于 供体移植物。 3) CD8+细胞改变调节反应，可能是通过产生额外的 调节性 T 细胞群。 本申请中提出的实验将重点关注调节性 T 细胞的特异性 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三个具体目标来检查不同的调节性 T 细胞 亚人群。第四个具体目标中的实验将使用有关其的信息 特异性比较调节性 T 细胞亚群的机制特性并 开发诊断方法来检测它们的存在。