Engineering DNA nanoparticles to create immune tolerance

描述（由申请人提供）：自身免疫性疾病的起源尚不清楚，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剂来阻断对感染和肿瘤的免疫。更好的治疗方法可能来自对诱导和维持免疫耐受性以抑制自身免疫的过程的更好理解，以及导致耐受性破坏的遗传和环境因素。我们的长期目标是阐明天然调节酶吲哚胺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。慢性I型干扰素(IFN？感知微生物感染的浆细胞样树突状细胞（pDCs）的产生是几种自身免疫性综合征的一个特征，这意味着持续的IFN？释放导致耐受性崩溃。然而干扰素吗?诱导一些树突状细胞（DC）亚群表达IDO，表达IDO的DC抑制T细胞反应，部分原因是通过稳定foxp3谱系CD4 T细胞（Tregs）的默认调节表型。因此，诱导IDO和激活Tregs的试剂可能改善自身免疫性疾病。最近，我们报道了在小鼠关节炎模型中，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免疫介导的关节损伤。对纳米颗粒货物DNA的耐受性反应通过IFN？和IDO，但不依赖于TLR9或IFN信号，从货物DNA中去除TLR9配体（CpG基序）不会影响耐受性反应，但会降低IFN的潜在毒性释放。在这个修订后的应用中，我们在罕见的先天免疫细胞中确定了DNA传感途径，该途径驱动对货物DNA的耐受性反应，并表明DNA纳米颗粒抑制多发性硬化症和1型糖尿病小鼠模型的自身免疫性疾病发作。我们的目标是阐明DNA纳米颗粒靶向的耐受性途径，并设计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。

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.