Regulation of asthma by Btk and family kinases

Btk 和家族激酶对哮喘的调节

• 批准号: 6831364
• 负责人: TOSHIAKI KAWAKAMI
• 金额: $ 42.01万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831364
• 关键词: DNA binding protein; antigen presentation; asthma; biological signal transduction; dendritic cells; disease /disorder model; flow cytometry; genetic regulation; genetically modified animals; helper T lymphocyte; immune response; immune tolerance /unresponsiveness; laboratory mouse; protein structure function; protein tyrosine kinase; western blottings

DESCRIPTION (provided by applicant): The incidence of allergic diseases, particularly asthma, has been increasing at the troubling pace of doubling during the last two decades in developed countries. Given the limited success in preventing and treating asthma and sometimes serious side effects of the current regimen with corticosteroids, it is obvious that we need to broaden our therapeutic choices for this and other allergic diseases. We and others have demonstrated the critical importance of Bruton's tyrosine kinase (Btk) in the activation of B and mast cells, two cell types that are involved in the pathophysiology of these diseases. When airway inflammation experiments, a disease model of asthma, were performed with btk -/- mice, we were surprised to find that btk -/- mice exhibited exaggerated inflammatory and immune responses. Immunization of these mice with ovalbumin induced an enhancement in production of not only type 2 helper T cell (Th2)-dependent IgE and IgG1 antibodies but also type 1 helper T cell (Th1)-associated IgG2a antibodies. These results suggest that mice lacking functional Btk tend to develop exaggerated immune responses characterized by both Th1 and Th2 cells upon exposure to inhaled allergen. Numerous studies point to the central role of dendritic cells (DCs) in orchestrating the Th development and activation. Our preliminary results demonstrated that Btk is expressed in bone marrow derived DCs (BMDCs) and splenic DCs and that BMDCs derived from btk -/- mice exhibit increased upregulation of MHC class II molecules in response to lipopolysaccharides, compared to wild-type cells. Our data also indicate that splenic DCs from btk -/- mice have a stronger ability to stimulate antigen-specific T cell proliferation and production of both Th1 and Th2 cytokines. These results prompt us to investigate roles of Btk in the development, maturation and function of DCs in the context of Th2-dependent airway inflammation as well as in non-Th2-dependent situations. Since BMDCs express Tec, a close relative of Btk, and several Src family kinases, that can regulate Btk activity, it will also be important to study roles of these kinases in DC biology. This is a poorly explored area in DC biology. Our efforts will hopefully identify novel targets for pharmaceutical intervention to treat asthma and other immune diseases.

描述(申请人提供)：在发达国家，过敏性疾病，特别是哮喘的发病率在过去20年中以令人不安的速度增加了一倍。鉴于目前的皮质类固醇疗法在预防和治疗哮喘方面的成功有限，有时还会产生严重的副作用，显然我们需要扩大对这种和其他过敏性疾病的治疗选择。我们和其他人已经证明了Bruton酪氨酸激酶(BTK)在B细胞和肥大细胞激活中的关键作用，这两种细胞类型参与了这些疾病的病理生理。当用BTK-/-小鼠进行哮喘的疾病模型--呼吸道炎症实验时，我们惊讶地发现BTK-/-小鼠表现出夸大的炎症和免疫反应。用卵清蛋白免疫这些小鼠，不仅诱导了依赖于2型辅助性T细胞(Th2)的IgE和IgG1抗体的产生，也诱导了1型辅助性T细胞(Th1)相关的IgG2a抗体的产生。这些结果表明，缺乏功能性BTK的小鼠在吸入变应原时往往会出现以Th1和Th2细胞为特征的过度免疫反应。大量研究表明，树突状细胞(DC)在协调Th的发育和激活中起着中心作用。我们的初步结果表明，BTK在骨髓来源的DC(BMDCs)和脾来源的DC中都有表达，与野生型细胞相比，BTK-/-小鼠来源的BMDCs对脂多糖的反应表现出更多的MHC II类分子上调。我们的数据还表明，来自BTK-/-小鼠的脾DC具有更强的刺激抗原特异性T细胞增殖和产生Th1和Th2细胞因子的能力。这些结果促使我们在Th2依赖的气道炎症和非Th2依赖的情况下，研究BTK在DC的发育、成熟和功能中的作用。由于BMDCs表达BTK的近亲Tec和几个调节BTK活性的Src家族蛋白，因此研究这些蛋白在DC生物学中的作用也将是非常重要的。这是DC生物学中一个很少被探索的领域。我们的努力有望为治疗哮喘和其他免疫性疾病的药物干预找到新的靶点。