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: 8827660
• 负责人: Hirohito Kita
• 金额: $ 53.57万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827660
• 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.

项目描述（申请人提供）：本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应答失调引起的。然而，仍然存在着几个基本问题。患者是如何产生这种适应不良的T细胞反应的？为什么不是所有血清IgE抗体可检测到的患者（如过敏性鼻结膜炎患者）都会发生哮喘？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细胞是如何发育的，以及哪些过敏原分子是关键参与者。我们现在假设，所谓的“Th2型免疫反应”的空气中的过敏原介导的两个不同的CD4+ T细胞亚群，即Th2细胞和滤泡T（Tfh）细胞，这是关键参与嗜酸性粒细胞炎症和gE抗体的生产，分别。我们还假设，外源性和内源性核糖核酸酶（RNases）参与病理性Th2细胞的发展。 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Th2型气道免疫应答链格孢和其他空气过敏原的作用。我们将利用细胞因子报告小鼠和基因缺陷小鼠，研究Th2细胞和Tfh细胞的区室化发育。在目的2中，我们将研究Tfh细胞在人类气道疾病中的作用。我们将描述血液CXCR5+CD4+ T细胞，Tfh细胞的人类对应物，在一组患者短豚草花粉热，并检查这些细胞在花粉热季节的动态变化。在目的3中，我们将确定链格孢属衍生的RNA酶和内源性RNA酶，如嗜酸性粒细胞衍生的神经毒素，在Th2型免疫应答的发展和恶化中的作用。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RNA酶和这些RNA酶缺陷的真菌。这三个目标所需的技术专长在Kita博士和他的合作者，真菌功能基因组学专家Lawrence博士的实验室中随时可用。 拟议的研究可能会提供一个更好的理解的基本机制的Th2型免疫力的发展，以空气中的过敏原，并将提供一个解释之间的解离强有力的气道炎症和IgE抗体的产生在某些患者过敏性气道疾病。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性分子。最终，这些研究将显著增强我们对过敏原诱导的气道炎症中涉及的关键细胞途径和分子的理解，从而允许鉴定用于开发治疗或预防哮喘和相关气道疾病的新治疗策略的关键靶点。