Molecular Mechanisms of HLA-DO in Antigen Processing

HLA-DO 抗原加工的分子机制

• 批准号: 8369154
• 负责人: Scheherazade Sadegh-Nasseri
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369154
• 关键词: Accounting; Address; Adverse effects; Affect; Allergens; Antigen Presentation; Antigen Presentation Pathway; Antigens; Autoimmune Diseases; B-Lymphocytes; Baculoviruses; Binding; Biochemical; Biological; Cathepsin H; Cathepsins; Cathepsins B; Cells; Collagen; Complex; DR1 gene; Dendritic Cells; Development; Dissociation; Epithelium; Epitopes; Felis catus; Future; Generations; HLA-DR1 Antigen; Histocompatibility Antigens Class II; Hypersensitivity; Immune system; Immunodominant Epitopes; Immunotherapeutic agent; Individual; Infection; Infectious Agent; Influenza; Insecta; Invaded; Kinetics; Knock-out; Knockout Mice; Knowledge; Length; Light; Major Histocompatibility Complex; Malignant Neoplasms; Mass Spectrum Analysis; Memory; Molecular; Mus; Outcome; Peptides; Play; Predisposition; Process; Proteins; Public Health; Reaction; Recombinants; Regulation; Research Personnel; Resistance; Role; Series; Surface Plasmon Resonance; System; T-Lymphocyte; Testing; Therapeutic Intervention; Thymus Gland; Vaccines; Work; antigen processing; base; cancer cell; design; fighting; in vivo Model; insight; microorganism; pathogen; response; tool; trend

DESCRIPTION (provided by applicant): The project described in this application addresses a mechanistic study aimed at understanding the mechanism of action of MHC class II accessory protein, HLA-DO and its role 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 include another MHC class II molecules HLA-DO and would explore its contribution to epitope capture and processing. Aim 1 would explore mechanistic aspects of how HLA-DO interacts with MHC II and HLA-DM, leading to regulation of peptide binding, and in Aim 2 we would investigate contributions of HLA-DO to epitope capture and editing from full length protein antigens and immunodominance. A clear understanding of HLA-DO function and its role in antigen processing and the selection of immunodominant epitopes, can guide the design of effective immunotherapeutics. PUBLIC HEALTH RELEVANCE: Development of effective vaccines and rational design of therapeutics for intervention in autoimmune diseases or cancer rely on good knowledge of key regions on a pathogen, or proteins from cancer cells or self that can be targeted by the immune system and are generally called antigenic epitopes. The immune system recognizes these epitopes and mounts specific responses through its cellular components, T cells and B cells. The specific cells become activated and fight the infection and then can retain the memory of the pathogen for future attacks (memory cells). Our study outlined in this application addresses understanding of the fundamental processes that regulate presentation of antigenic epitopes to the immune system. By knowing how different proteins involved in antigen processing can participate in this complex series of reactions, investigators can design biologics that are intelligently based and therefore can be highly effective while avoiding nonspecific side effects. Public Health

描述(由申请人提供)：本申请中描述的项目涉及一项旨在了解MHC II类辅助蛋白--人类白细胞抗原-DO的作用机制及其在产生免疫优势表位中的作用的机制研究。免疫优势是一种早已被认识到的现象，但到目前为止仍不清楚。众所周知，免疫系统关注的是极少数具有代表性的表位(称为免疫优势表位)，这些表位来自侵袭性致病物质，包括自身免疫性疾病、过敏和癌症中的抗原靶标。在所有这些情况下，免疫系统要么对MHC分子背景下的抗原肽做出积极反应，要么没有反应。最近我们对抗原呈递途径的了解进展表明，抗原处理和选择的步骤对呈递给T细胞的多肽库有重要影响。最近，我们在开发一种针对MHC II类分子的还原抗原处理系统方面取得了相当大的进展，该系统利用了II类抗原提呈途径的五个纯化蛋白成分。值得注意的是，这个系统产生了生理上相关的免疫优势表位，仅限于人类白细胞抗原-DR1。在这项提案中，我们将扩展这个MHC II系统，以包括另一个MHC II类分子HLA-DO，并将探索其对表位捕获和处理的贡献。目的1探讨人类白细胞抗原DO(HLADO)与MHC II和HLADM相互作用从而调节多肽结合的机制，目的2从全长蛋白抗原和免疫优势两个方面探讨HLADO在表位捕获和编辑中的作用。清楚了解人类白细胞抗原DO的功能及其在抗原处理和免疫优势表位选择中的作用，可以指导有效的免疫治疗药物的设计。 公共卫生相关性：开发有效的疫苗和合理设计干预自身免疫性疾病或癌症的治疗方法，依赖于对病原体关键区域的良好了解，或来自癌细胞或自身的可被免疫系统靶向的蛋白质，通常被称为抗原表位。免疫系统识别这些表位，并通过其细胞成分T细胞和B细胞产生特定的反应。特定的细胞被激活并与感染作斗争，然后可以保留病原体的记忆以备将来的攻击(记忆细胞)。我们在本申请中概述的研究涉及对调节抗原表位呈现给免疫系统的基本过程的理解。通过了解参与抗原处理的不同蛋白质如何参与这一复杂的一系列反应，研究人员可以设计基于智能的生物制剂，因此可以在避免非特异性副作用的同时高效。公共卫生