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：
9060891
负责人：
Andrew Lee Mellor
金额：
$ 37.5万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9060891
关键词：
Affect 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 Health ITGAM gene Immune Immune Tolerance Immunity Immunization Infection Inflammatory Insulin-Dependent Diabetes Mellitus Interferon Type I Interferon Type II Interferon-alpha Interferons Ligands Lymphoid Tissue Mediating Modeling Multiple Sclerosis Mus Myelogenous Onset of illness Ovalbumin Pathway interactions Phenotype Population Process Production Reagent 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 improved indoleamine joint injury microbial mouse model nanoparticle novel novel strategies paracrine prevent 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 (IFNαß) production by plasmacytoid dendritic cells (pDCs) that sense microbial infections is a feature of several autoimmune syndromes, implying that sustained IFNαß release drives tolerance breakdown. However IFNαß 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 IFNαß and IDO but were not dependent on TLR9 or IFNγ signaling accordingly, removing TLR9 ligands (CpG motifs) from cargo DNA did not affect tolerogenic responses but lowered potentially toxic release of IFNγ. 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。质子囊性树突状细胞（PDC）产生的慢性I型干扰素（IFNαß）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IFNαß释放驱动耐受性损坏。但是，IFNαß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（Treg）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免疫介导的关节损伤。通过IFNαß和IDO介导了对纳米颗粒货物DNA的耐受性反应，但不依赖于TLR9或IFNγ信号传导，从货物DNA中除去TLR9配体（CPG基序），从货物DNA中删除了耐受性反应，但降低了IFNγ的潜在毒性释放。在此修订后的应用中，我们确定了罕见的先天免疫细胞中的DNA感应途径，从而驱动对货物DNA的耐受性反应，并表明在多发性硬化症和I型糖尿病的小鼠模型中，DNA纳米颗粒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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation.

DOI：
10.1158/0008-5472.can-15-1456
发表时间：
2016-04-15
期刊：
Cancer research
影响因子：
11.2
作者：
Lemos H;Mohamed E;Huang L;Ou R;Pacholczyk G;Arbab AS;Munn D;Mellor AL
通讯作者：
Mellor AL

Stimulator of interferon genes agonists attenuate type I diabetes progression in NOD mice.

干扰素基因激动剂刺激剂可减轻 NOD 小鼠 I 型糖尿病的进展。

DOI：
10.1111/imm.13122
发表时间：
2019
期刊：
Immunology
影响因子：
6.4
作者：
Lemos,Henrique;Mohamed,Eslam;Huang,Lei;Chandler,PhillipR;Ou,Rong;Pacholczyk,Rafal;Mellor,AndrewL
通讯作者：
Mellor,AndrewL

Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?

DOI：
10.3389/fimmu.2017.01360
发表时间：
2017
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Mellor AL;Lemos H;Huang L
通讯作者：
Huang L

STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy?

DOI：
10.1586/1744666x.2015.995097
发表时间：
2015-01
期刊：
Expert review of clinical immunology
影响因子：
4.4
作者：
Lemos H;Huang L;McGaha T;Mellor AL
通讯作者：
Mellor AL

Co-treatments to Boost IDO Activity and Inhibit Production of Downstream Catabolites Induce Durable Suppression of Experimental Autoimmune Encephalomyelitis.

提高 IDO 活性并抑制下游分解代谢物产生的联合治疗可持久抑制实验性自身免疫性脑脊髓炎。

DOI：
10.3389/fimmu.2020.01256
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Lemos,Henrique;Mohamed,Eslam;Ou,Rong;McCardle,Caroline;Zheng,Xiaozhong;McGuire,Kris;Homer,NatalieZM;Mole,DamianJ;Huang,Lei;Mellor,AndrewL
通讯作者：
Mellor,AndrewL