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:
- 金额:$ 45.77万
- 依托单位:
- 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:
- 关键词:AcuteAffectAllelesAnterior uveitisAutoimmunityAutologousBehcet&aposs eye diseaseBindingBlindnessCD8-Positive T-LymphocytesCD8B1 geneCRISPR/Cas technologyCell surfaceCellsClonal ExpansionCloningDataDiseaseEndoplasmic ReticulumEpitopesEtiologyEyeGenerationsGenetic EpistasisGenetic PolymorphismGenotypeGoalsHLA-B AntigensHLA-B27 AntigenHLA-Bw51HaplotypesHealthHigh PrevalenceHumanImmune System DiseasesImmune responseImmune systemImmunityImmunogeneticsInflammationInsertional MutagenesisKnowledgeLigandsLiteratureMediatingMolecular TargetOutcomePathogenesisPathogenicityPathologicPatientsPeptidesPersonsPrediction of Response to TherapyPsoriasisPsoriatic ArthritisPublishingQuality of lifeResearchRiskSeriesT cell responseUveitisVariantViral Antigensdisorder controleconomic costeconomic impacteffector T cellenzyme activityexperimental studygene therapygenetic testinggenome editinghigh riskimmunogenicimmunogenicitypatient subsetspharmacologicpreventtargeted treatmenttherapeutic targettherapy 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/项目总结
ERAP 1的变异体调节疾病存在时几种形式的非感染性葡萄膜炎的风险-
相关的HLA I类,强烈表明迄今为止尚未证实的免疫优势的变化,
疾病的病因和预防。
本申请的总体目标是确定ERAP 1同种异型通过何种机制引起和
防止HLA I相关的葡萄膜炎。我们的长期目标是了解和治疗目标HLA类
我把自身免疫和葡萄膜炎联系起来。
我们的中心假设是同种异型ERAP 1改变了HLA I结合肽组,使其包括
当由疾病相关的HLA I呈递时是免疫原性的,其通过免疫原性抗原诱导或控制疾病。
免疫优势的改变。这项研究的基本原理是,ERAP 1介导的机制的理解,
HLA-I免疫的发病机制将使针对特定ERAP 1-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,我们将实现两个具体目标。在目标1中,我们将通过
同种异型ERAP 1 Hap 10在HLA-B*51+白塞葡萄膜炎(BU)中启动免疫功能障碍的机制
但通过一系列CRISPR/Cas9基因组编辑保护免受HLA-B*27+急性前葡萄膜炎(AAU)
实验这些实验将使我们能够确定其对HLA I限制性T细胞的功能贡献。
与这些疾病中的每一种相关的肽组及其对免疫原性或致耐受性
免疫反应。在目标2中,我们将建立HLA I限制性致病性表位如何依赖于同种异型-
通过利用来自活动性BU和AAU的克隆扩增的CD 8 T细胞实现特异性ERAP 1功能
用于细胞克隆、基因组编辑和免疫原性的功能评估。
我们预期以下结果:1)了解免疫原性和耐受性效应介导的
通过同种异型ERAP 1在两种高度疾病相关的HLA限制性环境中:HLA-B27和B51,
在这些情况下诱导或阻止免疫原性的表位,3)同种异型ERAP 1
调节自身免疫,并且对其活性的操纵调节致病性,
靶向ERAP 1酶活性的原理,或通过基因治疗。这将产生
通过鉴定分子靶点对该领域产生积极影响,从而设计治疗方法,
通过基因型定义的患者群体,并通过超越范围的机械理解,
BU和AAU与其他对人类健康有巨大影响的MHC-I-病,如IBD、银屑病和
牛皮癣关节炎
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Johannes Nowatzky其他文献
Johannes Nowatzky的其他文献
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{{ truncateString('Johannes Nowatzky', 18)}}的其他基金
Modulation of immunodominance in HLA class I associated uveitides
HLA I 类相关葡萄膜的免疫优势调节
- 批准号:
10345839 - 财政年份:2022
- 资助金额:
$ 45.77万 - 项目类别:
Unraveling the role of HLA-B51/ERAP1 in Behcet's eye disease
揭示 HLA-B51/ERAP1 在白塞氏眼病中的作用
- 批准号:
10534165 - 财政年份:2021
- 资助金额:
$ 45.77万 - 项目类别:
Unraveling the role of HLA-B51/ERAP1 in Behcet's eye disease
揭示 HLA-B51/ERAP1 在白塞氏眼病中的作用
- 批准号:
10328964 - 财政年份:2021
- 资助金额:
$ 45.77万 - 项目类别:
Harnessing monoclonal Treg for the treatment of autoimmune uveitis
利用单克隆 Treg 治疗自身免疫性葡萄膜炎
- 批准号:
8869794 - 财政年份:2015
- 资助金额:
$ 45.77万 - 项目类别:
Harnessing monoclonal Treg for the treatment of autoimmune uveitis
利用单克隆 Treg 治疗自身免疫性葡萄膜炎
- 批准号:
9045643 - 财政年份:2015
- 资助金额:
$ 45.77万 - 项目类别:
Harnessing monoclonal Treg for the treatment of autoimmune uveitis
利用单克隆 Treg 治疗自身免疫性葡萄膜炎
- 批准号:
9265471 - 财政年份:2015
- 资助金额:
$ 45.77万 - 项目类别:
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