Type I Interferon-Regulated T Helper Development

I 型干扰素调节 T 辅助细胞的开发

• 批准号: 7890297
• 负责人: John David FARRAR
• 金额: $ 51.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890297
• 关键词: Address; Affect; Allergic; Asthma; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Chronic; Data; Dendritic Cells; Development; Disease; Environment; GATA3 transcription factor; Grant; Helper-Inducer T-Lymphocyte; Hepatitis C; Human; Human Development; Hypersensitivity; Immune; Individual; Infection; Inflammation; Inflammatory; Inhalators; Interferon Type I; Interferons; Interleukin-12; Interleukin-13; Interleukin-4; Interleukin-5; Intervention; Life; Lung; Lung diseases; Maintenance; Mediating; Molecular; Multiple Sclerosis; Organism; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Process; Production; Regulation; Role; Shapes; T cell response; T-Lymphocyte; Th2 Cells; Virus Diseases; asthmatic patient; base; cytokine; efficacy testing; in vivo; novel; novel therapeutic intervention; public health relevance; response

DESCRIPTION (provided by applicant): CD4+ T helper (Th) cells regulate multiple aspects of adaptive cell mediated immunity through the secretion of specific subsets of cytokines. While their activities are critical in responses to pathogenic organisms, CD4+ T cells can also mediate pathologies associated with various inflammatory processes. Specifically, Th2 cells are the key subset of cells that orchestrate the inflammation of asthma through the secretion of the effector cytokines IL-4, IL-5, and IL-13. IL-4 drives Th2 development in CD4+ T cells through the induction of a key transcription factor GATA3. Unlike the innate cytokines IL-12 and IFN-3, we have recently demonstrated that type I interferon (IFN-1/2) inhibits the development and phenotype stability of IL-4-driven Th2 cells. We further demonstrate that IFN-1 blocks this developmental pathway by repressing GATA3 expression. Based on our findings, we propose that IFN-1/2 could block cytokine secretion of asthmatic Th2 cells and reverse the pathogenic effects in vivo. We will address this hypothesis with the following aims: Aim 1: Characterize the phenotype and function of Th2 cells undergoing redirection with IFN-1/2. Aim 2: Determine the molecular mechanism by which IFN-1/2 blocks GATA3 expression. Aim 3: Determine the ability of IFN-1/2 to inhibit phenotype stability and cytokine secretion from Th2 cells isolated from asthmatic patients. The results from these studies will form the basis for new therapeutic approaches to treat asthma involving IFN-1/2. PUBLIC HEALTH RELEVANCE: Asthma is a debilitating inflammatory disease of the lungs that affects millions of people worldwide. While various therapies are in place to provide temporary relief, and in some cases immediate life- saving intervention with inhalers, no treatment has been developed that blocks the chronic progression and maintenance of the disease. Asthma is an immune-mediated disorder caused by the inappropriate activation of CD4+ T cells to normally innocuous molecules in the environment. These activated T cells secrete soluble cytokines, such as interleukin-4, that activate a cascade of inflammatory processes in the lung. Thus, CD4+ T cells represent the primary target for reversing the pathogenesis of asthma. In our studies, we have found that a unique cytokine, type I interferon (IFN- a/b), potently blocks the development of these inflammatory T cells and inhibits their ability to secrete cytokines. Based on this observation, this proposal seeks to understand the mechanism by which IFN-a/b reverses these pathogenic T cells and will determine whether IFN-a/b can block cytokine secretion from these inflammatory T cells isolated from asthma sufferers. These studies will lay the groundwork for more effective and long-lasting treatment for allergy and asthma.

描述（由申请人提供）：CD4+ T 辅助 (Th) 细胞通过分泌特定的细胞因子亚群来调节适应性细胞介导的免疫的多个方面。虽然 CD4+ T 细胞的活性对于病原生物的反应至关重要，但它们也可以介导与各种炎症过程相关的病理。具体来说，Th2 细胞是通过分泌效应细胞因子 IL-4、IL-5 和 IL-13 来协调哮喘炎症的关键细胞亚群。 IL-4 通过诱导关键转录因子 GATA3 来驱动 CD4+ T 细胞中 Th2 的发育。与先天细胞因子 IL-12 和 IFN-3 不同，我们最近证明 I 型干扰素 (IFN-1/2) 抑制 IL-4 驱动的 Th2 细胞的发育和表型稳定性。我们进一步证明 IFN-1 通过抑制 GATA3 表达来阻断这一发育途径。根据我们的研究结果，我们提出 IFN-1/2 可以阻断哮喘 Th2 细胞的细胞因子分泌并逆转体内的致病作用。我们将通过以下目标来解决这一假设： 目标 1：表征经历 IFN-1/2 重定向的 Th2 细胞的表型和功能。目标 2：确定 IFN-1/2 阻断 GATA3 表达的分子机制。目标 3：确定 IFN-1/2 抑制哮喘患者分离的 Th2 细胞表型稳定性和细胞因子分泌的能力。这些研究的结果将构成涉及 IFN-1/2 的哮喘新治疗方法的基础。 公共卫生相关性：哮喘是一种使人衰弱的肺部炎症性疾病，影响着全世界数百万人。虽然有各种疗法可以提供暂时缓解，并且在某些情况下可以立即使用吸入器进行挽救生命的干预，但尚未开发出阻止疾病慢性进展和维持的治疗方法。哮喘是一种免疫介导的疾病，由 CD4+ T 细胞对环境中通常无害的分子的不适当激活引起。这些活化的 T 细胞分泌可溶性细胞因子，例如白细胞介素 4，可激活肺部的一系列炎症过程。因此，CD4+ T 细胞代表了逆转哮喘发病机制的主要靶标。在我们的研究中，我们发现一种独特的细胞因子，I 型干扰素 (IFN-a/b)，可以有效阻断这些炎症 T 细胞的发育并抑制其分泌细胞因子的能力。基于这一观察，该提案旨在了解 IFN-a/b 逆转这些致病性 T 细胞的机制，并将确定 IFN-a/b 是否可以阻止从哮喘患者中分离出的这些炎症 T 细胞分泌细胞因子。这些研究将为更有效、更持久的过敏和哮喘治疗奠定基础。