Alternaria and ribonucleases in Th2-type immunity

Th2 型免疫中的链格孢属和核糖核酸酶

• 批准号: 9054038
• 负责人: Hirohito Kita
• 金额: $ 38.42万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-20 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054038
• 关键词: Adjuvant; Allergens; Allergic; Allergic Disease; Allergic rhinitis; Alternaria; Ambrosia; Antibodies; Antibody Formation; Antigens; Asthma; BLR1 gene; Biological; Blood; CD4 Positive T Lymphocytes; Cells; Chronic; Collaborations; Data; Development; Disease; Dissociation; Enzymes; Eosinophil-Derived Neurotoxin; Eosinophilia; Genes; Goals; Hay fever; Health; Human; Hypersensitivity; IgE; Immune response; Immunity; Immunologics; In Vitro; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interleukin-5; Laboratories; Lung; Mediating; Modeling; Molecular; Mus; Organism; Pathologic; Pathway interactions; Patients; Prevalence; Production; Proteins; Pyroglyphidae; Recombinants; Reporter; Respiratory Tract Diseases; Ribonucleases; Role; Seasons; Serum; Source; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Technical Expertise; Testing; Th2 Cells; airborne allergen; airway inflammation; airway remodeling; allergic airway disease; asthmatic patient; atopy; cohort; cytokine; eosinophilic inflammation; functional genomics; fungus; in vivo; interest; mouse model; novel therapeutics; peripheral blood; prevent; research study; respiratory health; rhinoconjunctivitis

DESCRIPTION (provided by applicant): The long-term goal of this project is to better understand the immunologic mechanisms of asthma and allergic diseases. These diseases are generally thought to result from dysregulated immune responses to environmental proteins and organisms, which are mediated by Th2 cells. However, several fundamental questions still remain. How do patients develop such maladaptive T cell responses? Why don't all patients who have detectable serum IgE antibodies (e.g. patients with allergic rhinoconjunctivitis) develop asthma? By using the Alternaria fungus, which has been implicated in human asthma, we have been studying how allergen-specific CD4+ T cells develop and which allergen molecules are critically involved. We now hypothesize that the so-called "Th2-type immune response" to airborne allergens is mediated by two distinct CD4+ T cell subsets, namely Th2 cells and follicular T (Tfh) cells, which are critically involved in eosinophilic inflammation and gE antibody production, respectively. We also hypothesize that exogenous and endogenous ribonucleases (RNases) are involved in development of pathologic Th2 cells. In Aim 1, we will use mouse models and determine the roles of Th2 cells and Tfh cells in Th2-type airway immune responses to Alternaria and other airborne allergens. We will leverage cytokine reporter mice and gene-deficient mice and investigate the compartmentalized development of Th2 cells and Tfh cells. In Aim 2, we will investigate the roles of Tfh cells in human airway disease. We will characterize blood CXCR5+CD4+ T cells, a human counterpart of Tfh cells, in a cohort of patients with short ragweed hay fever and examine the dynamic changes in these cells during the hay fever season. In Aim 3, we will determine the roles of Alternaria-derived RNases and endogenous RNases, such as eosinophil-derived neurotoxin, in development and exacerbation of Th2 type immune responses. We will integrate data obtained from in vitro experiments and in vivo mouse models. Recombinant Alternaria RNases and the fungi deficient in these RNases will be examined. The technical expertise required for these three Aims is readily available in the laboratories of Dr. Kita and his collaborator, Dr. Lawrence, a fungal functional genomics expert. The proposed studies are likely to provide a better understanding of the fundamental mechanisms underlying the development of Th2-type immunity to airborne allergens and will provide an explanation for the dissociation between robust airway inflammation and IgE antibody production in certain patients with allergic airway disorders. The study will also likely identify potential key environmental and endogenous molecules that participate in the development of pathologic T cell responses in asthma. Ultimately, these studies will significantly enhance our understanding of the key cellular pathway(s) and molecule(s) involved in allergen- induced airway inflammation, allowing for identification of critical targets for development of novel therapeutic strategies to treat or to prevent asthma and related airway disorders.

描述（由申请人提供）：该项目的长期目标是更好地了解哮喘和过敏性疾病的免疫机制。这些疾病通常被认为是由 Th2 细胞介导的对环境蛋白质和生物体的免疫反应失调引起的。然而，一些基本问题仍然存在。患者如何产生这种适应不良的 T 细胞反应？为什么并非所有血清可检测到 IgE 抗体的患者（例如过敏性鼻结膜炎患者）都会患哮喘？通过使用与人类哮喘有关的链格孢属真菌，我们一直在研究过敏原特异性 CD4+ T 细胞如何发育以及哪些过敏原分子参与其中。我们现在假设，对空气中过敏原的所谓“Th2型免疫反应”是由两种不同的CD4+T细胞亚群介导的，即Th2细胞和滤泡T（Tfh）细胞，它们分别与嗜酸性炎症和gE抗体的产生密切相关。我们还假设外源性和内源性核糖核酸酶 (RNase) 参与病理性 Th2 细胞的发育。 在目标 1 中，我们将使用小鼠模型并确定 Th2 细胞和 Tfh 细胞在针对链格孢属和其他空气传播过敏原的 Th2 型气道免疫反应中的作用。我们将利用细胞因子报告小鼠和基因缺陷小鼠来研究 Th2 细胞和 Tfh 细胞的分化发育。在目标 2 中，我们将研究 Tfh 细胞在人类气道疾病中的作用。我们将在一群患有短豚草花粉热的患者中表征血液 CXCR5+CD4+ T 细胞（Tfh 细胞的人类对应物），并检查这些细胞在花粉热季节期间的动态变化。在目标 3 中，我们将确定链格孢衍生的 RNase 和内源性 RNase（例如嗜酸性粒细胞衍生的神经毒素）在 Th2 型免疫反应的发展和加剧中的作用。我们将整合从体外实验和体内小鼠模型获得的数据。将检查重组链格孢核糖核酸酶和缺乏这些核糖核酸酶的真菌。 Kita 博士及其合作者、真菌功能基因组学专家 Lawrence 博士的实验室很容易获得这三个目标所需的技术专业知识。 拟议的研究可能会更好地理解针对空气中过敏原的 Th2 型免疫发展的基本机制，并将为某些患有过敏性气道疾病的患者中强烈的气道炎症和 IgE 抗体产生之间的分离提供解释。该研究还可能确定参与哮喘病理性 T 细胞反应发展的潜在关键环境和内源分子。最终，这些研究将显着增强我们对涉及过敏原诱导的气道炎症的关键细胞途径和分子的理解，从而确定关键靶标，以开发治疗或预防哮喘和相关气道疾病的新治疗策略。