Mechanisms of CpG-Induced Inhibition of Allergic Asthma

CpG 诱导的过敏性哮喘抑制机制

• 批准号: 7008507
• 负责人: Eyal Raz
• 金额: $ 24.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008507
• 关键词: CpG islands; allergic pneumonitis; asthma; biological signal transduction; cell migration; cell proliferation; cellular immunity; cytokine; dendritic cells; flow cytometry; gene expression; genetically modified animals; helper T lymphocyte; immune response; immunogenetics; immunomodulators; interferon gamma; laboratory mouse; macrophage; phosphorylation; polymerase chain reaction; receptor expression; respiratory epithelium; tissue /cell culture; toll like receptor

DESCRIPTION (provided by applicant): T helper 2 (Th2) cells orchestrate allergic asthma. Inhibition of the Th2 response has been the target of many therapeutic strategies with only marginal success. Our recent studies have demonstrated that the administration of immunostimulatory sequence oligodeoxynucleotides (ISS-ODN, also known as CpGODN) inhibits Th2 responses and suppresses experimental asthma. Interestingly, these effects do not require a simultaneous antigen/allergen administration. The molecular pathways, which drive the ISS-induced inhibition of Th2 cells and the ISS-induced suppression of experimental asthma, have yet to be identified. We reason that the inhibition of the Th2 response by ISS-ODN is secondary to ISS-induced innate cytokines such as IFNs, IL-12 and IL-23 produced by TLR9 bearing APCs. Thus, we will focus our investigation in SA-1 on the signaling events originating at the cytokineR essential for Th2 cell function and survival. We will initially identify the altered cytokineR repertoire on Th2 cells, which makes them responsive to type 1 cytokines (e.g., IFNs) and resistant to type 2 cytokines (e.g., IL-4/IL-13). These studies will be followed by investigations aimed at exploring the changes in the transcriptional program in ISS-induced immunomodulated Th2 cells and the consequent phenotypic change that they undergo. Finally, we will address the ability of immunomodulated Th2 cells to proliferate and to resist pro-apoptotic signals upon allergen challenge. The information obtained in SA-1 will be used in SA-2 to further address the molecular events induced by ISS-ODN administration that lead to the inhibition of experimental asthma. Specifically, we will study the mechanisms by which ISS-ODN convey resistance of lung tissue to pro-asthmatic stimuli triggered by Th2 cells (e.g., IL-13) and the mechanisms by which ISS-ODN inhibits the homing/trafficking of Th2 cells into the airways. Finally, the fate of the ISS immunomodulated Th2 cells in the lung will be assessed. The information obtained in this application will be important to define as it could validate the use of ISS-ODN as a novel class of an immunomoduating agent and would facilitate its therapeutic use in the field of clinical allergy.

描述（由申请人提供）：辅助 T 2 (Th2) 细胞协调过敏性哮喘。抑制 Th2 反应一直是许多治疗策略的目标，但收效甚微。我们最近的研究表明，施用免疫刺激序列寡脱氧核苷酸（ISS-ODN，也称为 CpGODN）可以抑制 Th2 反应并抑制实验性哮喘。有趣的是，这些作用不需要同时施用抗原/过敏原。驱动 ISS 诱导的 Th2 细胞抑制和 ISS 诱导的实验性哮喘抑制的分子途径尚未确定。我们推断，ISS-ODN 对 Th2 反应的抑制是继发于 ISS 诱导的先天细胞因子，例如携带 TLR9 的 APC 产生的 IFN、IL-12 和 IL-23。因此，我们将把 SA-1 的研究重点放在源自对 Th2 细胞功能和生存至关重要的细胞因子 R 的信号转导事件上。我们将首先确定 Th2 细胞上改变的细胞因子 R 库，这使得它们对 1 型细胞因子（例如 IFN）敏感，并对 2 型细胞因子（例如 IL-4/IL-13）具有抵抗力。这些研究之后将进行旨在探索 ISS 诱导的免疫调节 Th2 细胞转录程序变化以及随之而来的表型变化的调查。最后，我们将探讨免疫调节 Th2 细胞在过敏原攻击时增殖和抵抗促凋亡信号的能力。 SA-1 中获得的信息将用于 SA-2 中，以进一步解决 ISS-ODN 给药诱导的分子事件，从而抑制实验性哮喘。具体来说，我们将研究 ISS-ODN 传递肺组织对 Th2 细胞（例如 IL-13）触发的促哮喘刺激的抵抗力的机制，以及 ISS-ODN 抑制 Th2 细胞归巢/运输到肺组织的机制。航空公司。最后，将评估肺部 ISS 免疫调节 Th2 细胞的命运。本申请中获得的信息对于定义非常重要，因为它可以验证 ISS-ODN 作为一类新型免疫调节剂的用途，并将促进其在临床过敏领域的治疗用途。