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

摘要 该项目的长期目标是为呼吸道炎症和过敏性哮喘开发更好的治疗方法。 哮喘的发病率和患病率在所有年龄组中继续增加，尽管在预防哮喘方面取得了进展。 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性 患者对特异性过敏原，表明预先存在的病理性TH 2反应， “重新编程或调节”，至少在某些情况下，导致永久治愈。我们最近发现了一个 小鼠浆细胞样DC（pDC）的亚群，其具有诱导耐受和主动诱导免疫耐受的能力。 调节性T（Treg）细胞（Muclidin Immunology 2012，Allergy 2013，Immunobiology 2015，JACI 2017）。这些 致耐受性pDC（tolpDC）亚群不诱导过敏性哮喘的特征，如气道高反应性（AHR） 而是可以在临床前模型中预防变应性气道疾病的发展。而且我们 进行了一系列的基因表达和表面标记研究，并成功地确定了一个同源 人血液样品中的致耐受性pDC群体。这些pDC亚群可以 诱导耐受性和促进Treg细胞诱导是多因素的。在具体目标1中，我们提出了一系列 研究进一步探索tolpDC的治疗应用，并通过以下方法充分表征其机制： 其tolpDC在AHR的临床前模型中诱导Treg细胞。在具体目标2中，我们将确定个体发育 利用转录因子敲除模型研究pDC的起源和发育 涉及常规DC和/或pDC发育和功能。最后，在具体目标3中，翻译研究 将进行分析，以解决tolpDC子集的功能或频率是否可能导致发展 和/或哮喘的严重程度。这些研究，基于强有力的初步数据，将集中在开发新的 过敏性哮喘是哮喘的一个主要类别，免疫调节受损。为了实现 根据这些结果，我们组建了一个团队，其中包括DC生物学领域的领先专家和临床研究中心主任。 肺科，以补充我们在临床前模型方面的丰富经验。项目的三个部分将最终 通过分析控制tolpDC的功能和稳态的因素是否影响 Treg细胞和效应T细胞应答之间的平衡，导致开发新的治疗药物， 过敏性疾病和哮喘的治疗策略。

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.