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知之甚少，尽管最近引入了新型免疫调节剂，但标准治疗仍然严重依赖于阻断对感染和肿瘤的免疫的免疫抑制剂。更好的治疗方法可能会出现在对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崩溃的遗传和环境因素的更好理解中。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？）浆细胞样树突状细胞（pDC）的生产，感觉微生物感染是几种自身免疫综合征的特征，这意味着持续的IFN？释放驱动容差分解。然而，IFN？诱导一些树突状细胞（DC）亚群表达IDO，并且表达IDO的DC部分地通过稳定Foxp3谱系CD4 T细胞（T细胞）的默认调节表型来抑制T细胞应答。因此，诱导IDO和激活Tcl3的试剂可以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。纳米颗粒货物DNA的耐受性反应是通过IFN？和IDO，但不依赖于TLR9或IFN？信号传导，因此，从货物DNA中去除TLR9配体（CpG基序）不影响致耐受性应答，但降低了IFN？的潜在毒性释放。在这个修订后的申请中，我们确定了罕见的先天免疫细胞中的DNA传感途径，该途径驱动对货物DNA的致耐受性反应，并表明DNA纳米颗粒抑制多发性硬化症和I型糖尿病小鼠模型中自身免疫性疾病的发作。我们的目标是阐明DNA纳米颗粒靶向的致耐受性途径，并将DNA纳米颗粒作为潜在的致耐受性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 (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.