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

促进过敏性哮喘呼吸耐受的细胞和途径的诱导

• 批准号: 9816485
• 负责人: OMID AKBARI
• 金额: $ 66.24万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816485
• 关键词: Address; Allergens; Allergic; Allergic Disease; Antigens; Aspergillus; Asthma; Back; Biocompatible Materials; Biology; Blood; Blood specimen; Categories; Cell surface; Cells; Clinical; Common Lymphoid Progenitor; Complement; Complement 1q; Complex; Data; Dendritic Cells; Development; Disease; Equilibrium; Eragrostis; Exposure to; Extrinsic asthma; FOXP3 gene; Frequencies; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Goals; Growth; Haplotypes; Health Care Costs; Homeostasis; Human; Hypersensitivity; Immunobiology; Immunology; Immunosuppression; Impairment; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin-2; Knock-out; Knowledge; Light; Lung; Mediating; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Pathologic; Pathway interactions; Patients; Peptides; Phenotype; Physiologic pulse; Population; Pre-Clinical Model; Prevalence; Process; Production; Property; Pulmonology; Pyroglyphidae; RUNX3 gene; Regulatory T-Lymphocyte; Respiratory Therapy; Series; Severities; Signal Transduction; Source; Specificity; Surface; Symptoms; System; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; age group; airway inflammation; allergic airway disease; base; cell type; clinical practice; conventional therapy; desensitization; design; effector T cell; experience; experimental study; immunogenic; immunoregulation; novel; novel therapeutics; prevent; progenitor; respiratory; response; symptom treatment; transcription factor; translational approach; translational study

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.

抽象的 该项目的长期目标是开发针对呼吸道炎症和过敏性哮喘的更好疗法。 尽管在哮喘防治方面取得了进展，但所有年龄段的哮喘发病率和患病率仍在持续增加 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 患者针对特定过敏原，表明先前存在的病理性 TH2 反应可以 “重新编程或调节”，至少在某些情况下导致永久治愈。我们最近确定了一个 鼠类浆细胞样 DC (pDC) 的子集，具有诱导耐受性和主动诱导耐受的能力 调节性 T (Treg) 细胞（粘膜免疫学 2012 年、过敏症 2013 年、免疫生物学 2015 年、JACI 2017 年）。这些 耐受性 pDC (tolpDC) 亚群不会诱发过敏性哮喘的特征，例如气道高反应性 (AHR) 但可以在临床前模型中预防过敏性气道疾病的发展。此外，我们 进行了一系列基因表达和表面标记研究并成功鉴定了同源 人类血液样本中的耐受性 pDC 群体。这些 pDC 子集的机制 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 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： 其能够在 AHR 临床前模型中诱导 pDC 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 的起源和发育 参与传统 DC 和/或 pDC 的发育和功能。最后在具体目标 3 中，转化研究 将执行以确定 tolpDC 子集的功能或频率是否可以负责开发 和/或哮喘的严重程度。这些研究以强有力的初步数据为基础，将重点开发新颖的 治疗过敏性哮喘，这是免疫调节受损的哮喘的一个主要类别。为了达到 根据这些结果，我们组建了一个团队，其中包括 DC 生物学的领先专家和临床主任 肺病学以补充我们在临床前模型方面的丰富经验。项目的三部分最终将 通过分析控制 tolpDC 功能和稳态的因素是否影响 Treg 细胞和效应 T 细胞反应之间的平衡，导致新型治疗方法的开发 过敏性疾病和哮喘的策略。