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

基本信息

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
项目类别：
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

项目摘要

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为呼吸道注射和过敏性哮喘开发更好的疗法。所有年龄段目的地的事件和哮喘患病率在目的地的进展中继续增加开发新疗法。当前的临床实践员工治疗策略可容忍过敏性针对特定过敏原的患者，表明先前存在的病理Th2反应可以是至少在某些情况下，“重编程或调节”，以永久性治疗。我们最近确定了具有影响公差并积极诱导的能力调节性T（Treg）细胞（粘膜免疫学2012，Allergy 2013，免疫生物学2015，JACI 2017）。这些耐受性PDC（TOLPDC）子集不会诱导过敏性哮喘（例如气道高反应（AHR））的特征但是，可以防止在临床前模型中发展过敏性气道疾病。而且，我们预先形成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耐受性PDC的种群。这些PDC子集可以使用的机制诱导耐受性并促进Treg细胞的诱导是多因素的。在特定目标1中，我们提出了一系列进一步探索TOLPDC的治疗应用的研究并通过 PDC在AHR的临床前模型中诱导Treg细胞。在特定目标2中，我们将确定个体发育并使用转录因子模型来研究这些PDC的起源和开发参与常规DC和/或PDC的开发和功能。最后，在特定的目标3中，翻译研究将执行以解决TOLPDC子集的功能或频率是否可能负责开发和/或哮喘的严重程度。这些研究基于强大的初步数据，将着重于开发新颖的研究过敏性哮喘的治疗，这是哮喘的主要类别，免疫调节受损。为了实现这些结果我们组建了一个团队，包括DC生物学领域的领先专家和临床主管肺部学以完成我们在临床前模型中的丰富经验。项目的三个部分最终将通过分析控制TOLPDC的功能和稳态的因素是否可以连接，影响 Treg细胞与效应T细胞反应之间的平衡，导致新治疗的发展过敏性疾病和哮喘的策略。