THE ROLE OF TH CELL SUBSETS AND ALLERGIC LUNG INFLAMMATI

TH 细胞亚群与过敏性肺部炎症的作用

• 批准号: 6537553
• 负责人: DALE T UMETSU
• 金额: $ 26.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537553
• 关键词: CD28 molecule; SCID mouse; antigen presentation; asthma; bronchomotion; cell population study; chemokine; cytokine; cytoprotection; helper T lymphocyte; immune tolerance /unresponsiveness; inflammation; laboratory mouse; monoclonal antibody; ovalbumin; respiratory hypersensitivity; tissue /cell culture; transforming growth factors

The long term goals of this project are to determine and understand the role of CD4 Th cell subsets in the development, maintenance, reduction, and prevention of allergen-induced airway hyperreactivity. We and others have shown that Th2 cells play a major role in producing and exacerbating allergic inflammation, and it has been assumed that Th cells with the "alternative" cytokine profile (i.e., Th1 cells) inhibit and prevent allergic inflammation in nonallergic individuals. Preliminary data in our laboratory however, indicate that antigen-specific Th1 cell lines when transferred into recipient mice, do not down regulate airway hyperreactivity but instead cause severe lung disease. This suggests that cell types other than Th1 cells (e.g., those producing TGF-beta), and other cellular processes may be involved in protective immune responses to allergens that down regulate and prevent allergic inflammatory responses in normal nonallergic individuals. The goals therefore of this proposal are to directly examine the capacity of Th1 cells and other types of regulatory cells to mitigate allergic inflammation and allergen- induced airway hyperreactivity. We will directly examine: 1. the role of Th1 and ThO cells in allergic airway hyperreactivity (a model for asthma). 2. the role of TGF-beta producing cells (established by gene transfer) in the regulation of airway hyperreactivity. 3. specific mechanisms that induce tolerance and inhibit airway hyperreactivity in mice rendered unresponsive to ovalbumin (e.g., the role of antigen presentation by B cells and by alveolar macrophages, and the role of costimulation with CTLA-4). We have established several unique models for airway hyperreactivity and intranasal tolerance, have assembled a broad range of reagents, and have exciting preliminary data to perform the proposed experiments. These innovative studies will expand our understanding of the complexity and diversity of Th cells and of immune responses that protect against allergy and asthma. They will provide the basis for development of new disease-modifying strategies to treat and potentially cure patients with allergy and asthma.

该项目的长期目标是确定和了解CD4细胞子集在过敏原诱导的气道高反应性的开发，维护，减少和预防中的作用。 我们和其他人表明，Th2细胞在产生和加剧过敏性炎症中起主要作用，并且已经假定具有“替代”细胞因子谱（即Th1细胞）的TH细胞抑制并预防非过敏个体的过敏性炎症。 但是，我们实验室中的初步数据表明，抗原特异性TH1细胞系转移到受体小鼠中时，请勿降低气道高反应性，而是引起严重的肺部疾病。 这表明，除Th1细胞（例如，产生TGF-β的人）以外的细胞类型以及其他细胞过程可能与对过敏原的保护性免疫反应有关，这些反应降低并防止正常非过敏个体中的过敏性炎症反应。 因此，该提案的目标是直接检查Th1细胞和其他类型的调节细胞的能力，以减轻过敏性炎症和过敏元引起的气道高反应性。 我们将直接检查：1。Th1和ThO细胞在过敏性气道高反应性（哮喘模型）中的作用。 2。TGF-β产生细胞（通过基因转移建立）在气道高反应性调节中的作用。 3。诱导耐受性和抑制小鼠气道高反应性的特定机制对卵蛋白具有无反应性（例如，B细胞和肺泡巨噬细胞的抗原表现以及用CTLA-4的costaimulation的作用）。我们已经建立了几种独特的模型，用于气道高反应性和鼻内耐受性，组装了广泛的试剂，并拥有令人兴奋的初步数据来执行提出的实验。 这些创新的研究将扩大我们对TH细胞的复杂性和多样性以及保护过敏和哮喘的免疫反应的理解。他们将为开发新的疾病改良策略的发展提供基础，以治疗和治疗患有过敏和哮喘的患者。