Epitope selection by HLA-DR

HLA-DR 表位选择

• 批准号: 7388846
• 负责人: JACK A GORSKI
• 金额: $ 29.77万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-09 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388846
• 关键词: Affect; Affinity; Algorithms; Alleles; Antigen Presentation; Antigens; Area; Attention; Autoimmune Responses; Binding; Characteristics; Class; Complex; Data; Epitopes; Genetic Polymorphism; Goals; HLA-DR Antigens; Histocompatibility Antigens Class II; Human; Immune; Immune response; Knowledge; Lead; Ligands; Major Histocompatibility Complex; Measures; Mediating; Minor; Modeling; Molecular Conformation; Numbers; Object Attachment; Outcome; Peptides; Phase Transition; Play; Positioning Attribute; Process; Property; Random Peptide Libraries; Range; Research; Role; Screening procedure; Side; Site; Solvents; Source; System; T-Lymphocyte; Testing; Transplantation; Vaccination; Vaccine Design; Vaccines; base; conformational conversion; conformer; design; insight; pathogen

DESCRIPTION (provided by applicant): The adaptive immune response starts with recognition of peptide antigens presented by class II molecules of the Major Histocompatibility Complex (MHC). Two outstanding features of these molecules are their polymorphism and the ability of each allele to bind a large panoply of peptides. The long-term goal of the research proposed here is to understand the function of the human class II MHC molecule HLA-DR in antigen presentation and the role of polymorphism therein. With a better understanding, progress can be made in two practical areas where HLA-DR plays a significant role, vaccination and transplantation. The short-term goal is to examine peptide binding at a basic level with the goal of understanding the process to the point that rational approaches to pathogen epitope identification can be established. Our model is that we are dissecting a complex system where one interaction is affected by other interactions. Our preliminary data indicates that this cooperativity between interactions is indeed an important aspect of the binding mechanism. In Aim 1 we investigate the phenomenon of cooperativity in more detail. We will determine whether the cooperativity we have observed in peptide residues that contact solvent extend to other residues. In Aim 2 we analyze further aspects of peptide binding including the possible role of hydrophobic nucleation sites and additional stability conferred through flanking residues. In Aim 3, the information gained in the two previous aims will be analyzed in the context of a hypothesis that there is a relation between intrinsic stability, cooperativity and a conformational change that allows stable binding of peptides of different apparent affinities. This is what allows the binding of a large number of peptides. Peptide binding takes place in the presence of an adjunct molecule, HLA-DM, which promotes the exchange of peptides. In Aim 4 we will determine structural characteristics that influence DM-mediated peptide exchange, thus providing insight as to what is an acceptable peptide for a particular HLA-DR allele. This may also lead to an understanding of the mechanism by which HLA-DM functions. Our model for this interaction is that HLA-DM puts the HLA-DR in a conformation in which the overall peptide-binding properties are changed and peptides interact based solely on their affinity.

描述（由申请方提供）：适应性免疫应答始于识别主要组织相容性复合物（MHC）II类分子呈递的肽抗原。这些分子的两个突出特征是它们的多态性和每个等位基因结合大量肽的能力。本文提出的研究的长期目标是了解人类II类MHC分子HLA-DR在抗原呈递中的功能以及多态性在其中的作用。有了更好的理解，可以在HLA-DR发挥重要作用的两个实际领域取得进展，即疫苗接种和移植。的 短期目标是在基本水平上检查肽结合，目的是理解该过程，以达到可以建立病原体表位鉴定的合理方法的程度。我们的模型是，我们正在解剖一个复杂的系统，其中一个相互作用受到其他相互作用的影响。我们的初步数据表明，这种相互作用之间的协同性确实是结合机制的一个重要方面。在目标1中，我们更详细地研究了协同性现象。我们将确定我们在接触溶剂的肽残基中观察到的协同性是否延伸到其他残基。在目标2中，我们分析了肽结合的进一步方面，包括疏水成核位点的可能作用和通过侧翼残基赋予的额外稳定性。在目标3中，将在假设内在稳定性、协同性和构象变化之间存在关系的背景下分析在前两个目标中获得的信息，所述构象变化允许不同表观亲和力的肽的稳定结合。这就是允许结合大量肽的原因。肽结合发生在辅助分子HLA-DM的存在下，其促进肽的交换。在目标4中，我们将确定影响DM介导的肽交换的结构特征，从而提供关于什么是特定HLA-DR等位基因可接受的肽的见解。这也可能导致对HLA-DM功能机制的理解。我们对这种相互作用的模型是，HLA-DM使HLA-DR处于一种构象，在这种构象中，整体肽结合特性发生变化，肽仅基于其亲和力相互作用。