Engineering DNA nanoparticles to create immune tolerance

设计 DNA 纳米粒子以产生免疫耐受

基本信息

批准号：
8578443
负责人：
Andrew Lee Mellor
金额：
$ 35.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578443
关键词：
Abbreviations Affect Antigen-Presenting Cells Antigens Apoptotic Arthritis Artificial nanoparticles Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity CD19 gene CD4 Positive T Lymphocytes Cells Chronic Clinical Combined Modality Therapy DNA Dendritic Cells Dinucleoside Phosphates Dioxygenases Disease Progression Disease model Elements Engineering Environmental Risk Factor Enzymes Experimental Autoimmune Encephalomyelitis Gene Activation Genes Genetic Goals ITGAM gene Immune Immune Tolerance Immunity Immunization Infection Inflammatory Insulin-Dependent Diabetes Mellitus Interferon Type I Interferons Kynurenine Ligands Lymphoid Tissue Mediating Modeling Multiple Sclerosis Mus Myelogenous Onset of illness Ovalbumin Pathway interactions Phenotype Population Process Production Reagent Regulatory T-Lymphocyte Reporting Risk Role Severity of illness Signal Transduction Syndrome T cell response T-Lymphocyte Testing Tissues Toxic effect Treatment Efficacy Tryptophan Vaccine Design Vaccines cytokine diphtheria toxin receptor improved indoleamine joint injury macrophage microbial mouse model nanoparticle novel novel strategies paracrine prevent public health relevance response standard care tumor

项目摘要

DESCRIPTION (provided by applicant): The origins of autoimmune diseases are poorly understood and standard treatments still rely heavily on immune suppressants that block immunity to infections and tumors despite the recent introduction of novel immune modulatory reagents. Better treatments will likely emerge from improved understanding of the processes that induce and maintain immune tolerance to suppress autoimmunity, and the genetic and environmental factors that cause tolerance breakdown. Our long-term goals are to elucidate the role of the natural regulatory enzyme indoleamine 2,3 dioxygenase (IDO) in suppressing autoimmunity, and to harness this pathway as a novel approach to treat autoimmune syndromes. Chronic type I interferon (IFN?¿) production by plasmacytoid dendritic cells (pDCs) that sense microbial infections is a feature of several autoimmune syndromes, implying that sustained IFN?¿ release drives tolerance breakdown. However IFN?¿ induces some dendritic cell (DC) subsets to express IDO, and DCs expressing IDO suppress T cell responses, in part by stabilizing the default regulatory phenotypes of Foxp3-lineage CD4 T cells (Tregs). Thus reagents that induce IDO and activate Tregs may ameliorate autoimmune diseases. Recently, we reported that treating mice with DNA nanoparticles suppressed T cell responses to immunization and alleviated immune-mediated joint injury in a mouse model of arthritis. Tolerogenic responses to nanoparticle cargo DNA were mediated via IFN?¿ and IDO but were not dependent on TLR9 or IFN¿ signaling accordingly, removing TLR9 ligands (CpG motifs) from cargo DNA did not affect tolerogenic responses but lowered potentially toxic release of IFN¿. In this revised application we identify the DNA sensing pathway in rare innate immune cells that drives tolerogenic responses to cargo DNA, and show that DNA nanoparticles inhibited autoimmune disease onset in mouse models of multiple sclerosis and type I diabetes. Our goals are to elucidate the tolerogenic pathway targeted by DNA nanoparticles and to engineer DNA nanoparticles as potential tolerogenic vaccines to treat and prevent autoimmune syndromes.

描述（由适用提供）：自身免疫性疾病的起源知之甚少，尽管最近引入了新型免疫调节剂，但标准治疗仍严重依赖于免疫抑制剂，这些免疫抑制剂阻止了免疫组织化学对感染和肿瘤。更好的治疗可能会从对诱导和维持免疫组织化学耐受性抑制自身免疫性的过程以及导致耐受性破坏的遗传和环境因素的过程中得以提高。我们的长期目标是阐明自然调节酶吲哚胺2,3二氧酶（IDO）在抑制自身免疫性中的作用，并利用这一途径作为治疗自身免疫综合征的新方法。慢性I型干扰素（IFN？¿）由浆细胞样树突状细胞（PDC）产生，感知微生物感染是几种自身免疫性综合征的特征，这意味着持续的IFN？释放驱动的耐受性破坏了。但是，IFN？¿诱导了一些树突状细胞（DC）亚群来表达IDO，而表达IDO抑制T细胞反应的DC部分是通过稳定Foxp3-Linege CD4 T细胞（Tregs）的默认调节表型。影响IDO并激活Treg的试剂可能会改善自身免疫性疾病。最近，我们报道说，用DNA纳米颗粒治疗小鼠，抑制了T细胞对免疫抑制的反应，并减轻了小鼠关节炎模型中的免疫介导的关节损伤。通过IFN？和IDO介导了对纳米颗粒货物DNA的耐受性反应，但并不依赖于TLR9或IFN？相应地信号传导，从货物DNA中删除TLR9配体（CPG基序），从货物DNA中删除了TLR9的配体（CPG基序），并未影响耐受性反应，而是降低了潜在的毒性毒性释放IFN。在此修订的应用中，我们确定了罕见的先天免疫力中的DNA感应途径，从而驱动对货物DNA的耐受性反应，并表明DNA纳米颗粒在多发性硬化症和I型糖尿病的小鼠模型中抑制了自身免疫性疾病的发作。我们的目标是阐明由DNA纳米颗粒靶向的耐受性途径，并将DNA纳米颗粒作为潜在的耐受性疫苗来治疗和预防自身免疫性综合征。