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的变体调节存在疾病存在下几种形式的非感染葡萄膜炎的风险 - 相关的HLA I类，强烈建议迄今未经证实的免疫变化，并影响疾病原因和保护。该应用的总体目的是确定ERAP1同型的机理以及防止与HLA I相关的葡萄膜炎。我们的长期目标是理解和热目标HLA类我关联了葡萄膜炎的自身免疫性。我们的中心假设是同型ERAP1改变了HLA I结合的肽，包括表位当与疾病相关的HLA I提出时，具有免疫原性，该I通过A影响或控制疾病免疫主持的变化。这项研究的基本原理是对ERAP1介导的机械理解 HLA I免疫力中的发病机理将实现针对特定ERAP1-HLA I-动炎的靶向治疗设计子集。根据这些考虑，我们将实施两个具体目标。在AIM 1中，我们将确定哪种机制ERAP1 HAP10在HLA-B*51+Behçet的葡萄膜炎（BU）中启动免疫功能障碍（BU）但是可以通过一系列CRISPR/CAS9基因组编辑来保护HLA-B*27+急性前葡萄膜炎（AAU）实验。这些实验将使我们能够定义其对HLA I限制的功能贡献与每种疾病有关的肽症及其对免疫原性或耐受性产生的影响免疫反应。在AIM 2中，我们将确定HLA I如何限制病原表位依赖于同种型。特定的ERAP1通过利用从活性BU和AAU的克隆扩展的CD8 T细胞的利用来函数细胞克隆，基因组编辑和免疫原性功能评估的患者。我们期望以下结果1）了解免疫原性和耐受作用介导的知识通过同型ERAP1在两个高度疾病的HLA限制环境中：HLA-B27和B51，2）在这些情况下影响或预防免疫原性的表位，3）原理证明异型ERAP1 调节自身免疫性，并操纵其活动调制致病性，可提供无可辩驳的用于靶向ERAP1酶活性的基本原理，或通过基因治疗。这将有一个通过鉴定分子靶标，对现场的积极影响，允许设计治疗由基因型定义的患者群体，并通过机械理解扩展到超出范围 BU和AAU会影响对人类健康的影响，例如IBD，牛皮癣和银屑病关节炎。