Modulation of immunodominance in HLA class I associated uveitides

HLA I 类相关葡萄膜的免疫优势调节

基本信息

批准号：
10557821
负责人：
Johannes Nowatzky
金额：
$ 45.77万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557821
关键词：
Acute Affect Alleles Anterior uveitis Autoimmunity Autologous Behcet&apos s eye disease Binding Blindness CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Cell surface Cells Clonal Expansion Cloning Data Disease Endoplasmic Reticulum Epitopes Etiology Eye Generations Genetic Epistasis Genetic Polymorphism Genotype Goals HLA-B Antigens HLA-B27 Antigen HLA-Bw51 Haplotypes Health High Prevalence Human Immune System Diseases Immune response Immune system Immunity Immunogenetics Inflammation Insertional Mutagenesis Knowledge Ligands Literature Mediating Molecular Target Outcome Pathogenesis Pathogenicity Pathologic Patients Peptides Persons Prediction of Response to Therapy Psoriasis Psoriatic Arthritis Publishing Quality of life Research Risk Series T cell response Uveitis Variant Viral Antigens disorder control economic cost economic impact effector T cell enzyme activity experimental study gene therapy genetic testing genome editing high risk immunogenic immunogenicity patient subsets pharmacologic prevent targeted treatment therapeutic target therapy design

项目摘要

ABSTRACT/PROJECT SUMMARY Variants at ERAP1 modulate the risk for several forms of non-infectious uveitis in the presence of disease- associated HLA class I, strongly suggesting a so far unproven change in immunodominance with impact on disease causation and protection. The overall objective of this application is to determine through which mechanism ERAP1 allotypes cause and protect from HLA I-associated uveitis. Our long-term goal is to understand and therapeutically target HLA class I associated autoimmunity in uveitis. Our central hypothesis is that allotypic ERAP1 alters the HLA I-bound peptidome to include epitopes that are immunogenic when presented by disease-relevant HLA I, which induces or controls disease through a change in immunodominance. The rationale for this study is that mechanistic understanding of ERAP1-mediated pathogenesis in HLA I immunity will enable targeted therapy design aimed at specific ERAP1-HLA I-uveitis subsets. Based on these considerations we will implement two specific aims. In Aim 1 we will determine through which mechanism the allotype ERAP1 Hap10 initiates immune dysfunction in HLA-B*51+ Behçet’s uveitis (BU) but protects from HLA-B*27+ acute anterior uveitis (AAU) via a series of CRISPR/Cas9 genome editing experiments. These experiments will allow us to define its functional contribution to the HLA I restricted peptidomes relevant to each of these disorders and their effect on the generation of immunogenic or tolerogenic immune responses. In Aim 2 we will establish how HLA I restricted pathogenic epitopes depend on allotype- specific ERAP1 function through the exploitation of clonally expanded CD8 T cells from active BU and AAU patients for cellular cloning, genome-editing and functional assessment of immunogenicity. We expect the following outcomes 1) knowledge of the immunogenic and tolerogenic effects mediated by allotypic ERAP1 in two highly disease-relevant HLA restriction contexts: HLA-B27 and B51, 2) identity of epitopes that induce or prevent immunogenicity in these contexts, 3) proof of principle that allotypic ERAP1 regulates autoimmunity and that manipulation of its activity modulates pathogenicity providing irrefutable rationale for targeting ERAP1 enzyme activity pharmacologically, or through gene therapy. This will have a positive impact on the field through the identification of molecular targets allowing the design of therapy for patient groups defined by genotypes, and through mechanistic understanding extending beyond the scope of BU and AAU to additional MHC-I-opathies with immense impact on human health, such as IBD, psoriasis, and psoriatic arthritis.

摘要/项目摘要 ERAP1 的变体在存在疾病的情况下调节多种形式的非感染性葡萄膜炎的风险 - 相关的 HLA I 类，强烈表明迄今为止未经证实的免疫优势变化对疾病的因果关系和保护。本申请的总体目标是确定 ERAP1 同种异型通过哪种机制引起和预防 HLA I 相关葡萄膜炎我们的长期目标是了解 HLA 类别并进行治疗。我与葡萄膜炎的自身免疫有关。我们的中心假设是，同种异型 ERAP1 改变了 HLA I 结合肽组，以包含以下表位：当由疾病相关的 HLA I 呈现时具有免疫原性，HLA I 通过以下方式诱导或控制疾病：这项研究的基本原理是对 ERAP1 介导的机制的理解。 HLA I 免疫的发病机制将使针对特定 ERAP1-HLA I 葡萄膜炎的靶向治疗设计成为可能子集。基于这些考虑，我们将通过实现目标 1 来实现两个具体目标。同种异型 ERAP1 Hap10 启动 HLA-B*51+ Behçet 葡萄膜炎 (BU) 免疫功能障碍的机制但通过一系列 CRISPR/Cas9 基因组编辑可预防 HLA-B*27+ 急性前葡萄膜炎 (AAU) 这些实验将使我们能够定义其对 HLA I 限制的功能贡献。与这些疾病相关的肽组及其对免疫原性或耐受性产生的影响在目标 2 中，我们将确定 HLA I 限制性致病表位如何依赖于同种异型。通过利用来自活性 BU 和 AAU 的克隆扩增 CD8 T 细胞实现特定 ERAP1 功能患者进行细胞克隆、基因组编辑和免疫原性功能评估。我们期望获得以下结果 1) 了解介导的免疫原性和耐受性效应通过同种异型 ERAP1 在两个与疾病高度相关的 HLA 限制环境中进行：HLA-B27 和 B51，2) 的身份在这些情况下诱导或防止免疫原性的表位，3）同种异型 ERAP1 的原理证明调节自身免疫并且操纵其活性调节致病性提供了无可辩驳的证据通过药理学或基因疗法靶向 ERAP1 酶活性的基本原理。通过识别分子靶标，设计治疗方案，对该领域产生积极影响由基因型定义的患者群体，并通过超越范围的机制理解 BU 和 AAU 涉及对人类健康具有巨大影响的其他 MHC-I 疾病，例如 IBD、牛皮癣和银屑病关节炎。