Engineering DNA nanoparticles to create immune tolerance

描述(申请人提供)：自身免疫性疾病的起源知之甚少，尽管最近引入了新的免疫调节试剂，但标准治疗仍然严重依赖免疫抑制药来阻断对感染和肿瘤的免疫。更好的治疗方法可能来自于更好地理解诱导和维持免疫耐受以抑制自身免疫的过程，以及导致耐受性崩溃的遗传和环境因素。我们的长期目标是阐明自然调节酶吲哚胺2，3双加氧酶(IDO)在抑制自身免疫中的作用，并利用这一途径作为治疗自身免疫综合征的新方法。由感知微生物感染的浆细胞样树突状细胞(PDCs)产生的慢性I型干扰素(干扰素α？)是几种自身免疫综合征的特征，这意味着持续的干扰素α？释放会导致耐受性崩溃。然而，干扰素αç诱导某些树突状细胞(DC)亚群表达IDO，而表达IDO的DC抑制T细胞反应，部分是通过稳定Foxp3系CD4T细胞(Treg)的默认调节表型。因此，诱导IDO和激活Treg的试剂可能会改善自身免疫性疾病。最近，我们报道了用DNA纳米颗粒治疗小鼠，抑制了T细胞对免疫的反应，并减轻了关节炎小鼠模型中免疫介导的关节损伤。对纳米粒载体DNA的耐受反应是通过干扰素α？和干扰素γ介导的，但不依赖于TLR9或干扰素γ信号。因此，去除TLR9配体(CpG基序)不会影响耐受性反应，但会降低干扰素DNA的潜在毒性释放。在这一修订的应用中，我们确定了稀有的先天性免疫细胞中驱动对Cargo DNA的耐受性反应的DNA传感途径，并表明DNA纳米颗粒抑制了多发性硬化症和I型糖尿病小鼠模型的自身免疫性疾病的发生。我们的目标是阐明DNA纳米颗粒靶向的耐受途径，并将DNA纳米颗粒作为潜在的耐受疫苗来治疗和预防自身免疫综合征。

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.