PROCESSING OF ANTIGENS FOR HLA-RESTRICTED PRESENTATION

处理 HLA 限制性呈递的抗原

• 批准号: 2064643
• 负责人: Elizabeth D Mellins
• 金额: $ 10.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2064643
• 关键词: MHC class II antigen; Retroviridae; antigen presentation; antigen presenting cell; bacterial antigens; chromosomes; clone cells; cytotoxic T lymphocyte; gene complementation; gene expression; genetic mapping; histocompatibility antigens; human genetic material tag; human subject; hybrid cells; major histocompatibility complex; molecular cloning; monoclonal antibody; mutant; peptides; phagocytosis; protein transport

The long term objective of this application is to elucidate pathways for generating an MHC molecule/peptide complex within an antigen presenting cell. The specific aims of this proposal are to functionally and genetically characterize a group of mutant antigen presenting cells, which are unable to present a variety of soluble antigens to class II restricted T cells but can present a peptide antigen. The approaches are: to use proteolytic digests of antigen and DR restricted peptide specific T cell clones to more extensively evaluate the mutants' ability to present antigen; to determine whether the mutants are defective in antigen processing via the endocytic pathway; to use somatic cell hybrids to determine how many complementation groups exist among 8 obligate independent presentation defective mutants; to determine whether human non-lymphoid cells and murine lymphoid cells can complement the defect(s) in the mutants; to determine whether the affected gene(s) map to X chromosome or the HLA-D region of chromosome 6; and to isolate phenotypically similar mutants using retroviral insertional mutagenesis as a tool for eventual cloning of the mutant gene(s). In addition, isolation of other antigen processing mutants by immunoselection with antigen specific cytolytic T cells will be pursued. These studies may lead to a better understanding of MHC restricted antigen processing/presentation and may thus provide insights into the pathophysiology of HLA associated diseases in which MHC restricted T cells are likely to play a role.

该应用的长期目标是阐明途径 在抗原呈递物中产生 MHC 分子/肽复合物 细胞。 该提案的具体目标是在功能上和 从基因上表征了一组突变的抗原呈递细胞， 无法向 II 类限制性抗原呈递多种可溶性抗原 但T细胞可以呈递肽抗原。 方法是：使用 抗原和 DR 限制性肽特异性 T 细胞的蛋白水解消化 克隆以更广泛地评估突变体的呈现能力 抗原;确定突变体是否存在抗原缺陷 通过内吞途径进行加工；使用体细胞杂交体 确定 8 个专性组中存在多少个互补组 独立表达缺陷突变体；来判断是否是人类 非淋巴细胞和鼠淋巴细胞可以弥补缺陷 在突变体中；确定受影响的基因是否映射到 X 染色体或6号染色体的HLA-D区域；并隔离 使用逆转录病毒插入诱变产生表型相似的突变体 最终克隆突变基因的工具。 另外，隔离 通过抗原免疫选择产生其他抗原加工突变体 将追求特异性溶细胞T细胞。 这些研究可能会导致 更好地了解 MHC 限制性抗原加工/呈递以及 因此可能为 HLA 相关的病理生理学提供见解。 MHC 限制性 T 细胞可能在其中发挥作用的疾病。