Role of DM in Generation of Immunodominant Epitope(s)

DM 在免疫显性表位生成中的作用

• 批准号: 8692628
• 负责人: Scheherazade Sadegh-Nasseri
• 金额: $ 42.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692628
• 关键词: Address; Adverse effects; Affect; Antigen Presentation Pathway; Antigens; Autoimmune Diseases; B-Lymphocytes; Binding; Biological; Cathepsin L; Cathepsins; Cathepsins B; Cell-Free System; Cells; Collagen; Complex; DR1 gene; Data; Development; Dissociation; Epithelium; Epitopes; Exopeptidase; Future; Generations; Goals; HLA-DR1 Antigen; HLA-DR4 Antigen; Histocompatibility Antigens Class II; Hypersensitivity; Immune; Immune system; Immunodominant Epitopes; Immunotherapeutic agent; Individual; Infection; Infectious Agent; Influenza; Influenza A Virus, H5N1 Subtype; Interferon Type II; Invaded; Knowledge; Laboratories; MHC Class II Genes; Malaria; Malignant Neoplasms; Mass Spectrum Analysis; Memory; Molecular; Mus; Nature; Oxidoreductase; Pathway interactions; Peptide Hydrolases; Peptides; Process; Proteins; Proteolysis; Research Personnel; Resistance; Role; Sulfhydryl Compounds; System; T-Lymphocyte; TCF Transcription Factor; TNFRSF10A gene; Testing; Therapeutic Intervention; Vaccine Design; Vaccines; Work; antigen processing; base; cancer cell; design; disulfide bond; fighting; hemagglutinin (306-318); new technology; parent grant; pathogen; response

DESCRIPTION (provided by applicant): The project described in this application addresses a mechanistic study aimed at understanding the steps involved in generation of immunodominant epitopes. Immunodominance is a phenomenon that has long been recognized but yet remains unclear to date. It is well known that the immune system focuses on and responds to very few representative epitopes (referred to as immunodominant epitopes) from invading pathogenic insults ranging from such as infectious agents and, antigenic targets in autoimmune diseases, allergy, and cancer. In each all these cases, the immune system either responds positively or fails to respond to antigenic peptides in the context of MHC molecules. Recent advances in our understanding of the antigen presentation pathway have shown that the steps of antigen processing and selection critically influence the peptide repertoire presented to T-cells. Recently, we have made considerable progress in developing a reductionist antigen processing system for MHC class II molecules that utilizes five purified protein components of the class II antigen presentation pathway. Notably, this system yielded physiologically relevant immunodominant epitopes restricted to HLA-DR1. In this proposal, we will extend this MHC II system to another MHC class II molecules HLA-DR4 and would explore steps involved in epitope capture and antigen processing. Overall, we propose to dissect underlying factors of T-cell immunodominance. Aim 1 would explore the temporal relationship between antigen capture and processing. In Aim 2, we would investigate epitope hierarchy and the role for DM, and in Aim 3, we would analyze contributions of HLA-DO to epitope capture and editing. Hence, knowledge of the identity of immunodominant epitopes, and a clear understanding of how they are generated inside cells, can guide the design of effective immunotherapeutics.

描述（由申请人提供）：本申请中描述的项目致力于机械研究，旨在了解免疫显性表位生成所涉及的步骤。免疫优势是一种早已被认识到但迄今为止仍不清楚的现象。众所周知，免疫系统关注并响应来自入侵病原体的极少数代表性表位（称为免疫显性表位），其范围包括感染因子以及自身免疫性疾病、过敏和癌症中的抗原靶点。在所有这些情况下，免疫系统要么对 MHC 分子中的抗原肽做出积极反应，要么无法做出反应。我们对抗原呈递途径理解的最新进展表明，抗原加工和选择的步骤严重影响呈递给 T 细胞的肽库。最近，我们在开发用于 MHC II 类分子的还原性抗原加工系统方面取得了相当大的进展，该系统利用了 II 类抗原呈递途径的五种纯化蛋白成分。值得注意的是，该系统产生了仅限于 HLA-DR1 的生理相关免疫显性表位。在本提案中，我们将将此 MHC II 系统扩展到另一个 MHC II 类分子 HLA-DR4，并将探索涉及表位捕获和抗原加工的步骤。总的来说，我们建议剖析 T 细胞免疫优势的潜在因素。目标 1 将探索抗原捕获和处理之间的时间关系。在目标 2 中，我们将研究表位层次结构和 DM 的作用，在目标 3 中，我们将分析 HLA-DO 对表位捕获和编辑的贡献。因此，了解免疫显性表位的身份以及清楚地了解它们在细胞内如何产生，可以指导有效免疫治疗的设计。