Molecular Mechanisms of HLA-DO in Antigen Processing

HLA-DO 抗原加工的分子机制

基本信息

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
项目类别：
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

项目摘要

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介绍了一项机械研究，旨在了解MHC II类辅助蛋白，HLA-DO及其在产生免疫剂量表位的作用的作用机理。免疫主管是一种长期以来已被认可的现象，但尚不清楚迄今为止。众所周知，免疫系统关注并反应着很少有代表性表位（称为免疫主流表位），从侵入诸如感染剂和自身免疫性疾病，镇静剂和癌症的抗原靶标的入侵的病原体损伤中。在所有这些情况下，免疫系统要么在MHC分子的背景下对抗原肽做出积极反应，要么无法反应。我们对抗原表现途径的理解的最新进展表明，抗原加工和选择的步骤严重影响呈现给T细胞的肽库。最近，我们在为MHC II类分子开发还原剂抗原加工系统方面取得了长足进展，该抗原加工系统利用了II类抗原表现途径的五种纯化蛋白质成分。值得注意的是，该系统产生了限于HLA-DR1的生理相关免疫主导表位。在此提案中，我们将扩展该MHC II系统，以包括另一个MHC II类HLA-DO分子，并将探索其对表位捕获和加工的贡献。 AIM 1将探讨HLA-DO如何与MHC II和HLA-DM相互作用的机械方面，从而导致肽结合的调节，并且在AIM 2中，我们将研究HLA-DO对epiTope捕获和从全长蛋白质抗原和编辑中的贡献免疫主持。对HLA-DO功能及其在抗原加工中的作用以及免疫主导表位的选择可以指导有效的免疫治疗剂的设计。公共卫生相关性：开发有效的疫苗和用于干预自身免疫性疾病或癌症的治疗疗法的合理设计取决于对病原体的关键区域的良好知识，或者是癌细胞或自我的蛋白质，可以由免疫系统靶向，通常称为抗原表位。免疫系统通过其细胞成分，T细胞和B细胞识别这些表位，并安装特定的反应。特定细胞被激活并抗击感染，然后可以保留病原体的记忆以进行未来攻击（记忆细胞）。我们在本申请中概述的研究涉及对调节免疫系统抗原表位的基本过程的理解。通过了解参与抗原加工的不同蛋白质如何参与这一复杂的反应，研究人员可以设计智能的生物制剂，因此可以非常有效，同时避免非特异性副作用。公共卫生