Innate cytokine responses that regulate autoimmunity

调节自身免疫的先天细胞因子反应

基本信息

批准号：
7650695
负责人：
HARVEY CANTOR
金额：
$ 36.55万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7650695
关键词：
Accounting Antigen Presentation Antigens Autoantigens Autoimmune Responses Autoimmunity Binding Biological Process Cells Complex Cross Presentation Dendritic Cells Development Disease Endosomes Exons Experimental Autoimmune Encephalomyelitis Fibronectins Funding Gene Expression Generations Genes Genetic Grant IRAK1 gene Immune response In Vitro Infection Interferon-alpha Investigation Knock-in Mouse Lead Mediating Microglia Modeling Molecular Multiple Sclerosis Mus Mutant Strains Mice Mutation Osteogenesis Pathway interactions Peptides Phosphorylation Physiological Population Production Protein Isoforms Proteins Qa-1 Antigen RNA Research Role Signal Pathway Signal Transduction Site Specific qualifier value T-Lymphocyte Testing Therapeutic Effect Translations Up-Regulation Vascularization base cell type cytokine insight interferon alpha receptor interferon alpha-beta receptor mannose receptor mutant novel therapeutic intervention osteopontin prevent public health relevance receptor research study response selective expression uptake

项目摘要

DESCRIPTION (provided by applicant): Progress in the research funded by this grant has led to the discovery that the Osteopontin gene specifies two distinct isoforms through differential translation of a single Opn RNA species: a cytokine in T cells and a critical intracellular protein expressed in dendritic cells. We have shown that Opn expression in plasmacytoid dendritic cells is essential for production of this cell's signature cytokine- interferon alpha. We have recently discovered that robust Th17 responses depend on the ability of a newly-defined intracellular Opn isoform- Opn-i - to inhibit secretion of IL-27 by DC. We have also defined an Opn-i-dependent interaction that prevents efficient development of Th17 responses. Interferon alpha/beta receptor (IFNAR)-dependent inhibition of Opn-i expression releases the brakes on IL-27 secretion and inhibits the Th17 response to self-peptides. Definition of the impact of this IFNAR:Opn-i axis on the Th1 and Th17 response has provided new insight into the basis for the therapeutic effects of IFN-I in Multiple Sclerosis and other Th17 diseases, as well as a rationale for new therapeutic approaches that engage this IFNAR:Opn-i pathway. We propose experiments (1) to define the genetic mechanism resulting in generation of Opn-i and Opn-s expression in DC and T cells; (2) to define the interaction between Opn-i and the MyD88 signaling module in plasmacytoid DC leading to IFN1 expression and enhanced Th1 development; (3) to analyze Opn-dependent interactions in conventional DC that regulate antigen presentation and Th17 development and (4) to generate mice that selectively express distinct Opn isoforms so that we may determine the contribution of Opn isoforms to the immune response to foreign and self antigens in the context of Experimental Autoimmune Encephalomyelitis (EAE mu model of MS. PUBLIC HEALTH RELEVANCE: The Osteopontin (Opn) gene is important in diverse biological processes, including immune responses, vascularization and bone formation, through its interaction with different cell types. Our recent discovery of the contribution of distinct secreted and intracellular isoforms of Opn to the generation of Th17 and Th1 subsets fills an important gap in understanding the genesis of these subsets in normal and autoimmune responses. We will generate mutant mice that express the intracellular or secreted Opn isoform for analysis of the contribution of each to protection again infection and in a murine model of Multiple Sclerosis.

描述（由申请人提供）：该赠款资助的研究的进展导致发现，发现骨桥蛋白基因通过单个OPN RNA物种的差分翻译指定了两种不同的同工型：T细胞中的细胞因子和树突状细胞中表达的关键细胞内蛋白。我们已经表明，浆细胞类树突状细胞中的OPN表达对于产生该细胞的签名细胞因子干扰素α至关重要。我们最近发现，强大的Th17响应取决于新定义的细胞内OPN同工型OPN-I-通过DC抑制IL-27分泌的能力。我们还定义了一种依赖OPN-I的相互作用，以防止TH17响应的有效发展。干扰素α/β受体（IFNAR）依赖性抑制OPN-I表达可释放IL-27分泌的制动器，并抑制TH17对自肽的反应。 IFNAR：OPN-I轴对TH1和TH17响应的影响的定义为IFN-I在多发性硬化症和其他TH17疾病中的治疗效果的基础提供了新的见解，以及一种与IFNAR：OPN-I途径相关的新治疗方法的基本原理。我们提出了实验（1）来定义导致DC和T细胞中OPN-I和OPN-S表达产生的遗传机制；（2）定义等立纤溶酶DC中OPN-I与MyD88信号模块之间的相互作用，从而导致IFN1表达并增强Th1发育； (3) to analyze Opn-dependent interactions in conventional DC that regulate antigen presentation and Th17 development and (4) to generate mice that selectively express distinct Opn isoforms so that we may determine the contribution of Opn isoforms to the immune response to foreign and self antigens in the context of Experimental Autoimmune Encephalomyelitis (EAE mu model of MS. PUBLIC HEALTH RELEVANCE: The Osteopontin （OPN）在不同的生物学过程中很重要，包括免疫反应，血管形成和骨骼形成，它与我们最近发现了OPN对TH17和TH1产生的独特分泌和细胞内同类型的贡献。分泌的OPN同工型用于分析每个人对再次保护感染的贡献以及多发性硬化症的鼠模型。