The costimulatory T-cell molecule ICOS as a novel therapeutic target for allergic airway disease

共刺激T细胞分子ICOS作为过敏性气道疾病的新型治疗靶点

• 批准号: 57198407
• 负责人: Professor Dr. Andreas Hutloff
• 金额: --
• 依托单位: Campus Virchow-Klinikum (CVK) (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/57198407?language=en
• 关键词: costimulatory; cell; molecule; ICOS; novel

T cells initiate and maintain allergic airway inflammation by facilitating cellular infiltration and humoral immune responses. Activation, differentiation, and effector cell function of T cells is directed by so-called costimulatory molecules that deliver critical signals modulating the antigen-specific signal of the T-cell receptor (TCR). Considering their pivotal impact on T-cell regulation, costimulatory molecules are promising targets for therapeutic intervention in allergic diseases. Many of these costimulatory molecules have been identified only recently. So far, little is known about their specific role in the regulation of the immune response, especially for allergic airway inflammation. According to current understanding, the Inducible Co-Stimulatory T cell molecule, ICOS, is one of the most promising candidates for an in vivo blocking strategy to treat allergic airway inflammation, because it specifically regulates the effector phase of Th2 cells and is important for the regulation of immunoglobulin production by B cells. We are especially interested in the local production of allergen-specific IgE in lung tissues. Only recently we showed that ICOS is mainly involved in this process. However, the exact cell interactions, time, and mode of ICOS costimulation during allergic airway inflammation is still not fully understood. To learn more about the role of T and B cells for the pathophysiology of airway inflammation, we want to establish a mouse model for allergic airway inflammation in which it will be possible to track antigen-specific T and B cells in vivo at any stage of the allergic response and analyse them on a single-cell level. This system will be crucial to defining the exact role of ICOS costimulation in allergic airway inflammation, which is a prerequisite for the development of therapeutic strategies. As a new therapeutic strategy, we plan to interfere with ICOS costimulation using blocking monoclonal antibodies in our mouse model and test different routes and time points of application. Studies will also include a chronic airway inflammation model and delayed treat-ment regime to mimick more closely the clinical setting in patients. Taken together, this project will deliver important information on the pathophysiology of allergic airway inflammation and the applicability of T cell costimulation blockade for the treatment of allergic diseases.

T细胞通过促进细胞渗透和体液免疫反应来启动和维持过敏性呼吸道炎症。T细胞的激活、分化和效应细胞功能是由所谓的共刺激分子指导的，这些分子传递关键信号来调节T细胞受体(TCR)的抗原特异性信号。考虑到它们对T细胞调节的关键影响，共刺激分子是变态反应性疾病治疗干预的有前途的靶点。其中许多共刺激分子直到最近才被发现。到目前为止，人们对它们在免疫反应调节中的具体作用知之甚少，特别是对过敏性呼吸道炎症的调节。根据目前的了解，可诱导共刺激T细胞分子ICOS是体内阻断治疗过敏性呼吸道炎症的最有前景的候选分子之一，因为它特异性地调节Th2细胞的效应相，并对B细胞免疫球蛋白的产生起重要调节作用。我们对肺组织中过敏原特异性IgE的局部产生特别感兴趣。直到最近，我们才发现ICOS主要参与了这一过程。然而，变态反应性呼吸道炎症过程中ICOS共刺激的确切细胞相互作用、时间和模式仍不完全清楚。为了更多地了解T和B细胞在呼吸道炎症的病理生理学中的作用，我们想要建立一个过敏性气道炎症的小鼠模型，在该模型中，可以跟踪体内过敏反应的任何阶段的抗原特异性T和B细胞，并在单细胞水平上对它们进行分析。这一系统对于确定ICOS共刺激在过敏性呼吸道炎症中的确切作用至关重要，这是制定治疗策略的先决条件。作为一种新的治疗策略，我们计划在我们的小鼠模型中使用封闭的单抗来干扰ICOS的共刺激作用，并测试不同的应用路线和时间点。研究还将包括慢性呼吸道炎症模型和延迟治疗方案，以更接近于患者的临床环境。综上所述，该项目将提供关于过敏性呼吸道炎症的病理生理学和T细胞共刺激阻断用于治疗过敏性疾病的适用性的重要信息。

项目成果

Prenatal allergen exposures prevent allergen‐induced sensitization and airway inflammation in young mice

产前过敏原暴露可预防幼鼠过敏原诱导的过敏和气道炎症

• DOI: 10.1111/j.1398-9995.2011.02775.x
• 发表时间: 2012
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Gerhold;A. Avagyan;E. Reichert;C. Seib;D.V. Van;E.O. Luger;A. Hutloff;E. Hamelmann
• 通讯作者: E. Hamelmann