MECHANISM OF ACTION OF HLA CLASS I PEPTIDES

HLA I 类肽的作用机制

• 批准号: 6100158
• 负责人: ALAN MICHAEL KRENSKY
• 金额: $ 18.51万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6100158
• 关键词: MHC class I antigen; anergy; binding proteins; biological signal transduction; calcium flux; chemical binding; cytotoxic T lymphocyte; drug delivery systems; human subject; human tissue; immune tolerance /unresponsiveness; intracellular transport; laboratory rabbit; leukocyte activation /transformation; monoclonal antibody; peptide analog; phlebotomy; phosphoproteins; phosphorylation; protein sequence; stereoisomer; stress proteins; synthetic peptide; transplant rejection; western blottings; yeast two hybrid system

The ultimate goal of this Program is to induce and maintain immunologic tolerance in organ transplant patients. To this end, we propose to define the mechanism of action of HLA derived peptides and to optimize them for clinical use. Project 1 focuses on further elucidation of the mechanism of action of the HLA-B2702 derived peptide that has already been shown to inhibit T lymphocyte responses both in vitro and in vivo, and has been advanced to phase II clinical trials. In aim 1, a 46kD protein that is decreased in phosporylation upon T cell activation in the presence of presence of peptide will be identified and characterized, and the signal transduction pathway involved will be investigated. Intracellular localization of peptide will be characterized by microscopy. In aim 2, heat shock protein 70 family members that bind this peptide will be further characterized and new ligand(s) will be identified using the yeast two hybrid approach. In aim 3, peptides will be optimized for use in vivo. The use of D-amino acids, continuous infusion or release, local delivery, and non-peptidic analogs will be explored. This Project parallels Project 2, which will investigate a class II derived peptide, relies on Project 3 for gene therapy approaches, and is heavily dependent on Core B for novel peptides.

该计划的最终目标是诱导和维护 器官移植患者的免疫耐受性。为此，我们 建议定义HLA衍生肽的作用机理 并优化它们以供临床使用。项目1专注于进一步 阐明了HLA-B2702的作用机理 已经证明可以抑制T淋巴细胞的肽 在体外和体内响应，并且已转向相位 II临床试验。在AIM 1中，一种46KD蛋白的降低 在存在的情况下，T细胞激活时的阳光 肽将被识别和表征，并信号 将研究涉及的转导途径。细胞内 肽的定位将以显微镜为特征。在AIM 2中， 热休克蛋白70个结合该肽的家庭成员将是 进一步的特征和新的配体将使用 酵母两种混合方法。在AIM 3中，将优化肽 在体内使用。使用D-氨基酸，连续输注或释放， 将探索本地传递和非肽类似物。这个项目 Parallels项目2，该项目将研究II类衍生肽， 依赖于基因治疗方法的项目3，并且很严重 取决于核B的新肽。