Induction of cells and pathways that promote respiratory tolerance in allergic asthma

摘要 该项目的长期目标是开发更好的呼吸道炎症和过敏性哮喘治疗方法。 哮喘的发病率和流行率在所有年龄段都在继续增加，尽管在 开发新的治疗方法。目前的临床实践采用治疗策略来耐受过敏 患者对特定过敏原的反应，表明先前存在的病理性TH2反应可能是 “重新编程或管制”，至少在某些情况下，导致根治。我们最近发现了一种 小鼠浆细胞样树突状细胞亚群，具有诱导耐受和主动诱导的能力 调节性T(Treg)细胞(粘膜免疫学2012、过敏2013、免疫生物学2015、JACI 2017)。这些 耐受性PDC(TolpDC)亚群不会诱发过敏性哮喘的特征，如呼吸道高反应性(AHR) 而是可以在临床前模型中预防过敏性呼吸道疾病的发展。此外，我们 进行了一系列的基因表达和表面标记研究，并成功地鉴定了一种同源 人类血液样本中耐受性pDC的数量。这些PDC子集可以通过哪些机制 诱导耐受和促进Treg细胞的诱导是多因素的。在具体目标1中，我们提出了一系列 进一步探索TolpDC的治疗应用，并通过以下方式充分表征其机制 在AHR的临床前期模型中，TOL PDCs诱导Treg细胞。在具体目标2中，我们将确定个体发育 并利用转录因子的敲除模型研究这些pDC的起源和发展。 参与常规DC和/或PDC的开发和运作。最后，具体目标3：翻译研究 将执行，以解决tolpDC子集的功能或频率是否可能对开发负责 和/或哮喘的严重程度。这些研究基于强大的初步数据，将专注于开发小说 治疗过敏性哮喘，这是哮喘的一个主要类别，免疫调节受损。为了实现 这些结果我们组建了一个团队，其中包括DC生物学领域的一位领先专家和临床科主任 肺病学以补充我们在临床前模型方面的丰富经验。项目的三个部分最终将 通过分析控制TolpDC功能和动态平衡的因素是否影响 Treg细胞和效应T细胞反应之间的平衡，导致新的治疗方法的发展 针对过敏性疾病和哮喘的策略。

Abstract The long-term goal of this project is to develop better therapies for respiratory inflammation and allergic asthma. The incidence and prevalence of asthma continues to increase in all age groups despite progress in the development of new treatments. Current clinical practice employs therapeutic strategies to tolerize allergic patients against specific allergens, indicating that pre-existing pathological TH2 responses can be “reprogrammed or regulated”, resulting, at least in some cases, in permanent cures. We recently identified a subset of murine plasmacytoid DCs (pDCs) that have the capacity to induce tolerance and actively induce regulatory T (Treg) cells (Mucosal Immunology 2012, Allergy 2013, Immunobiology 2015, JACI 2017). These tolerogenic pDC (tolpDC) subsets do not induce features of allergic asthma such as airway hyperreactiviy (AHR) but can instead prevent the development of allergic airway disease in pre-clinical models. Moreover, we preformed a series of gene expression and surface marker studies and successfully identified a homologous population of tolerogenic pDCs in human blood samples. The mechanisms by which these pDC subsets can induce tolerance and promote induction of Treg cells are multi-factorial. In Specific Aim 1, we proposed series of studies to further explore the therapeutic application of tolpDCs and to fully characterize the mechanisms by which tol pDCs induce Treg cells in pre-clinical models of AHR. In Specific Aim 2 we will determine the ontogeny and study the origin and the development of these pDCs, utilizing knock out models of transcriptional factors involve in conventional DCs and/or pDC development and function. Finally in Specific Aim 3, translational studies will be performed to address if function or frequency of tolpDC subsets could be responsible for the development and/or severity of asthma. These studies, based on strong preliminary data, will focus on developing novel therapy for allergic asthma, a major category of asthma, with impaired immunoregulation. In order to achieve these results we have assembled a team including a leading expert in DC biology and the chief of clinical pulmonology to complement our extensive experience in pre-clinical models. The three parts of project will finally be connected by analyzing whether the factors that control the function and homeostasis of tolpDCs, influence the balance between Treg cells and effector T cell responses, leading to the development of novel therapeutic strategies for allergic diseases and asthma.